6-heteroaryloxy- or 6-aryloxy-quinoline-2-carboxamides and method of use

ABSTRACT

and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, R2, and R3 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Nav1.7 and/or Nav1.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/239,554, filed on Aug. 17, 2016, which is a continuation of U.S.patent application Ser. No. 14/613,579, filed on Feb. 4, 2015 and thatissued as U.S. Pat. No. 9,452,986 on Sep. 27, 2016, which claimspriority to U.S. Provisional Patent Application Ser. No. 61/936,397,filed Feb. 6, 2014, all of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION Technical Field

The invention relates to 6-heteroaryloxy- or6-aryloxy-quinoline-2-carboxamides that are sodium channel (e.g.,Na_(v)1.7 and Na_(v)1.8) blockers, useful in treating diseases andconditions mediated and modulated by the voltage-gated sodium channels.Additionally, the invention relates to compositions containing compoundsof the invention and processes of their preparation.

DESCRIPTION OF RELATED TECHNOLOGY

The voltage-gated sodium channels (VGSCs, Na_(v)1.x) contribute to theinitiation and propagation of action potentials in excitable tissuessuch as nerve and muscle by modulating the influx of sodium ions.Na_(v)1.7, one of nine sodium channel isoforms, is preferentiallyexpressed in the peripheral nervous system where it acts as a thresholdchannel for action potential firing in neurons (Cummins T R, et al.Expert Rev Neurother 2007; 7:1597-1612. Rush A M, et al. J Physiol 2007;579:1-14.). A wealth of evidence connects abnormal activity of sodiumchannels in the peripheral nervous system to the pathophysiology ofchronic pain (Goldin A L, et al. Neuron 2000; 28:365-368. Dib-Hajj S D,et al. Annu Rev Neurosci 2010; 33:325-347.). Polymorphisms in SCN9A, thegene that encodes Na_(v)1.7, cause human pain disorders arising fromeither gain-of-function or loss-of-function mutations of the channel.Clinically, VGSC blockers have proven useful in the management of pain,but their utility is often limited by incomplete efficacy and poortolerability. Local anesthetics (e.g., lidocaine), anti-arrhythmicagents (e.g., mexilitene), and anti-convulsants (e.g., lamotrigine) areall relatively weak (IC₅₀ values in the high micromolar range),non-selective (versus Na_(v)1.x subtypes and other ion channels) VGSCblocking agents identified without prior knowledge of their moleculartargets.

The VGSCs are integral plasma membrane proteins composed of a large (260kDa) α-subunit and one or more smaller β-subunits (Hargus N J et al.Expert Opin Invest Drugs 2007; 16:635-646). Nine α-subunits(Na_(v)1.1-Na_(v)1.9) and four β-subunits (β1-β4) have been identifiedin mammals. The various VGSC subtypes exhibit diverse functionalproperties and distinct expression patterns, suggesting differentialinvolvement in transmission of specific signals. Na_(v)1.7, Na_(v)1.8and Na_(v)1.9 are expressed predominantly in the peripheral nervoussystem in humans and rodents (Waxman S G Brain 2010; 133:2515-2518). Thebiophysical characteristics of Na_(v)1.7 suggest a role in initiation ofaction potentials, while Na_(v)1.8 is a major contributor to theupstroke of action potentials in sensory neurons. Na_(v)1.9 produces apersistent current that is involved in setting the resting membranepotential.

The Na_(v)1.7 isoform is expressed in both small and large diameter DRGneurons, as well as in sympathetic neurons, and in peripheral axonaltermini of neurons processing pain. Na_(v)1.7 is up-regulated inpreclinical models of inflammatory and neuropathic pain, includingdiabetic neuropathy (Dib-Hajj S D, et al. Nat Rev Neurosci. 2013;14:49-62. Hong S, et al. Journal of Biological Chemistry. 2004;279:29341-29350. Persson A K, et al. Exp Neurol. 2011; 230:273-279.).Na_(v)1.7 has been shown to accumulate in painful neuromas, such asthose in amputees with phantom limb pain, and in painful dental pulp(Beneng K, et al. BMC Neurosci. 2010; 11:71. Dib-Hajj S D, et al. NatRev Neurosci. 2013; 14:49-62). Rare human genetic conditions involvingsingle-nucleotide polymorphisms in SCN9A, the gene encoding forNa_(v)1.7 highlight its importance in pain pathways. Bi-allelicgain-of-function mutations (enhancing channel activity and increasingthe excitability of DRG neurons) produce severe pain syndromes withdominant genetic inheritance. Mutations that hyperpolarize activationvoltage dependence (i.e., facilitate channel opening and increase theexcitability of DRG neurons) result in inherited erythromelalgia (IEM),a condition characterized by excruciating burning pain, attacks ofedema, increased skin temperature and flushing of the skin affecting thedistal extremities. Similarly, polymorphisms that impair inactivation ofthe channel and enhance persistent current lead to paroxysmal extremepain disorder (PEPD), a condition wherein episodic severe perineal,perioccular and paramandibular pain is accompanied by autonomicmanifestations such as skin flushing usually in the lower body (Waxman SG Nature 2011472:173-174. Dib-Hajj S D, et al. Brain 2005;128:1847-1854.). By contrast, bi-allelic loss-of-function mutationspreventing the production of functional Na_(v)1.7 channels producedchannelopathy-associated congenital insensitivity to pain (CIP). CIPpatients do not perceive or understand pain even when confronted withextreme pain stimuli such as bone fractures, surgery, dentalextractions, burns, and childbirth.

The role of Na_(v)1.7 in pain has been confirmed in knockout studies.Global deletion of Na_(v)1.7 in knockout mice causes a disruption ofnormal eating behavior due to a deficit in olfaction, resulting inlethality shortly after birth (Nassar M A, et al. Proc Natl Acad Sci USA2004; 101:12706-12711). A conditional Na_(v)1.7 knockout inNa_(v)1.8-expressing DRG neurons abrogated inflammation-induced pain anddiminished responses to mechanical insult, but neuropathic paindevelopment was not affected (Nassar M A, et al. Mol Pain 2005;1:24-31). However, ablation of Na_(v)1.7 in both sensory and sympatheticneurons recapitulated the pain-free phenotype seen in CIP patients,abolishing inflammatory and neuropathic pain without causing any overtautonomic dysfunction (Minett M S, et al. Nat Commun 2012; 3:791).Na_(v)1.7-deficient sensory neurons also failed to release substance Pin the spinal cord or to display synaptic potentiation in the dorsalhorn of the spinal cord in response to electrical stimulation of thesciatic nerve (Minett M S, et al. Nat Commun 2012; 3:791).

The level of preclinical validation for the Na_(v)1.8 isoform as atarget for pain is also compelling. Complementary to Na_(v)1.7 in itsbiophysical and functional profile, one Na_(v)1.8 isoform is expressedin nociceptive trigeminal neurons, in the vast majority of DRG neurons,and in peripheral free nerve endings (Shields S D, et al. Pain 2012;32:10819-10832). An evaluation of Na_(v)1.8-null mice demonstrated thatthis channel carries the majority of current underlying the upstroke ofaction potential in nociceptive neurons. Knockout studies furtherimplicate Na_(v)1.8 in visceral, cold, and inflammatory pain, but not inneuropathic pain. However, assessment of Na_(v)1.8 antisenseoligonucleotides, also suggested involvement of Na_(v)1.8 in thedevelopment and maintenance of neuropathic pain, in addition toconfirming the relevance of the channel in inflammatory pain (Momin A,et al. Curr Opin Neurobiol 2008; 18:383-388. Rush A M, et al. J Physiol2007; 579:1-14. Liu M et al. Pain Med 12 Suppl 2011; 3:593-99.). Humangain-of-function mutations in Na_(v)1.8 were recently identified inpatients with SFN who were all negative for mutations in Na_(v)1.7(Faber C G, et al. Proc Natl Acad Sci USA. 2012; 109:19444-19449).

While the literature offers preclinical validation for Na_(v)1.7 andNa_(v)1.8 as pain targets, multiple challenges confront the discoveryand development of small molecule blockers. The potency needed forefficacy, the levels of selectivity versus the various isoforms requiredfor acceptable therapeutic index, and the relevance of state- anduse-dependent activity are not well understood. Although compounds andmechanisms exist that are used clinically to treat pain, there is needfor new compounds that can effectively treat different types of pain.Pain of various types (e.g., inflammatory pain, post-surgical pain,osteoarthritis pain, knee pain, lower back pain, neuropathic pain)afflicts virtually all humans and animals at one time or another, and asubstantial number of medical disorders and conditions produce some sortof pain as a prominent concern requiring treatment. As such, it would beparticularly beneficial to identify new compounds for treating thevarious types of pain.

SUMMARY

The invention is directed to 6-heteroaryloxy- or6-aryloxy-quinoline-2-carboxamides having a structure of formula (I):

or a pharmaceutically acceptable salt, ester, amide, or radiolabelledform thereof, wherein:

R¹ is selected from the group consisting of phenyl and monocyclic 5- or6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroarylis unsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsselected from the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, halogen, cyano, —NO₂, —OR^(1a), —OC(O)R^(1a),—OC(O)N(R^(b))(R^(3a)), —SR^(1a), —S(O)R^(2a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —C(O)OR^(1a),—C(O)N(R^(b))(R^(3a)), —N(R^(b))(R^(3a)), —N(R^(a))C(O)R^(1a),—N(R^(a))C(O)O(R^(1a)), —N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—NO₂, —N(R^(b))S(O)₂(R^(2a)),—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(a))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),(CR^(4a)R^(5a))_(m)—N(R^(b))S(O)₂(R^(2a)), cyano-C₁-C₆-alkyl, andhalo-C₁-C₆-alkyl;

-   -   R^(a) and R^(b), at each occurrence, are each independently        hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   R^(1a) and R^(3a), at each occurrence, are each independently        hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   R^(2a), at each occurrence, is independently C₁-C₆-alkyl or        halo-C₁-C₆-alkyl;    -   R^(4a) and R^(5a), at each occurrence, are each independently        hydrogen, halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   m, at each occurrence, is independently 1, 2, 3, 4, or 5;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, and -G²;

R³ is selected from the group consisting of hydrogen, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(CR^(4b)R^(5b))_(n)—NO₂,—(CR^(4b)R^(5b))_(n)—OR^(1b), —CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]₂,—(CR^(4b)R^(5b))_(n)—OC(O)R^(1b),—(CR^(4b)R^(5b))_(n)—OC(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—SR^(1b), —(CR^(4b)R^(5b))_(n)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)R^(1b), —(CR^(4b)R^(5b))_(n)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))C(O)N(R^(b))(—(CR^(4b)R^(5b))_(n)—OR^(1b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G⁴),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G³), —(CR^(4b)R^(5b))_(n)—C(O)G⁴,—(CR^(4b)R^(5b))_(n)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—N(R^(b))(G³),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(n)—N(R^(b))S(O)₂R^(2b), —S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(n)—(R^(a))C(O)N(R^(a))C(O)N(R^(b))(R^(3b)), -G²,—(CR^(4b)R^(5b))_(n)-G⁴-G²-G⁶, -G¹, —(CR^(4b)R^(5b))_(n)-G³,—CH[C(O)N(R^(b))(R^(3b))][—(CR^(4b)R^(5b))_(n)-G³], cyano-C₁-C₆-alkyl,and halo-C₁-C₆-alkyl;

-   -   R^(1b) and R^(3b), at each occurrence, are each independently        hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   R^(2b), at each occurrence, is independently C₁-C₆-alkyl or        halo-C₁-C₆-alkyl;    -   R^(4b) and R^(5b), at each occurrence, are each independently        hydrogen, halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   n, at each occurrence, is independently 1, 2, 3, 4, or 5;    -   G¹ and G³ are each independently aryl or heteroaryl; wherein G¹        and G³ are each independently unsubstituted or substituted with        1, 2, 3, 4, or 5 substituents selected from the group consisting        of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano,        halo-C₁-C₆-alkyl, halogen, nitro, —N(R^(c))₂,        —N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c), —C(O)OR^(c),        —C(O)N(R^(c))₂, —SO₂R^(d), and —SO₂N(R^(c))₂;    -   G², G⁴ and G⁶ are each independently 3-6-membered-cycloalkyl,        3-6-membered-cycloalkenyl, or 4-10-membered-heterocycle; wherein        G², G⁴ and G⁶ are each independently unsubstituted or        substituted with 1, 2, 3, 4, or 5 substituents selected from the        group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,        benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen,        nitro, oxo, —N(R^(c))₂, —N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c),        —C(O)OR^(c), —C(O)N(R^(c))₂, —SO₂R^(d), —SO₂N(R^(c))₂, and        phenyl, wherein phenyl and the phenyl ring of benzyl are        optionally substituted with 1, 2, 3, or 4 C₁-C₆-alkyl, halogen,        or C₁-C₆-alkoxy;        -   R^(c) at each occurrence, is independently hydrogen,            C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, cycloalkyl,            cycloalkyl-C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; wherein said            aryl, the aryl of aryl-C₁-C₆-alkyl, the cycloalkyl, and the            cycloalkyl of cycloalkyl-C₁-C₆-alkyl are independently            unsubstituted or substituted with 1, 2 3, 4, or 5            substituents independently selected from the group            consisting of C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen;    -   R^(d) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl; or    -   R², R³ and the nitrogen atom to which they are attached form a        4-8-membered-monocylic heterocycle, 6-11-membered-bicyclic        heterocycle, 10-12-membered-tricyclic heterocycle,        7-11-membered-spirocyclic heterocycle or 8-11-membered-bicyclic        heteroaryl comprised of a monocyclic heterocycle fused to a        monocyclic heteroaryl, wherein said 4-8-membered monocyclic        heterocycle, said 6-11-membered-bicyclic heterocycle, said,        10-12-membered-tricyclic heterocycle, said        7-11-membered-spirocyclic heterocycle and said        8-11-membered-bicyclic heteroaryl are unsubstituted or        substituted with 1, 2, 3, 4, or 5 substituents selected from the        group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,        halogen, cyano, —NO₂, —OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c),        —OG¹³, —OC(O)R^(1c), —OC(O)N(R^(b))(R^(3c)), —SR^(1c),        —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴,        —S(O)₂N(R^(b))(R^(3c)), —S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),        —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴, —C(O)R^(1c), —C(O)G¹⁴,        —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)), —N(R^(b))(R^(3c)),        —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴, —N(R^(a))C(O)O(R^(c)),        —N(R^(a))C(O)N(O)(R^(b))(R^(3c)), (CR^(4c)R^(5c))_(p)—NO₂,        —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),        —(CR^(4c)R^(5c))_(p)—OR^(1c),        —(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),        —(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),        —(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),        —(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),        —(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),        —(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R³),        —(CR^(4c)R^(5c))_(p)—C(O)R^(1c),        —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),        —(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),        —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),        —(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),        —(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),        —(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),        —(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),        —(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,        —(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,        —(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo,        C¹-C⁶-alkoxyimino and halo-C₁-C₆-alkyl;    -   R^(1c) and R^(3c), at each occurrence, are each independently        hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   R^(2c), at each occurrence, is independently C₁-C₆-alkyl or        halo-C₁-C₆-alkyl;    -   R^(4c) and R^(5c), at each occurrence, are each independently        hydrogen, halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;    -   p, at each occurrence, is independently 1, 2, 3, 4, or 5;    -   G¹¹ and G¹³ are each independently phenyl or        5-6-membered-heteroaryl; wherein G¹¹ and G¹³ are each        independently unsubstituted or substituted with 1, 2, 3, 4, or 5        substituents selected from the group consisting of C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl,        halo-C₁-C₆-alkyl, halogen, nitro, —N(R^(e))₂,        —N(R^(e))C(O)R^(e), —OR^(e), —C(O)R^(e), —C(O)OR^(e),        —C(O)N(R^(e))₂, —SO₂R^(f), and —SO₂N(R^(e))₂;    -   G¹², and G¹⁴ are each independently 3-6-membered-cycloalkyl,        3-6-membered-cycloalkenyl, or 4-10-membered-heterocycle, wherein        G¹² and G¹⁴ are each independently unsubstituted or substituted        with 1, 2, 3, 4, or 5 substituents selected from the group        consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, benzyl,        cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,        oxo, —N(R^(e))₂, —N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f),        —OR^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f),        —SO₂N(R^(e))₂, and phenyl, wherein phenyl and the phenyl ring of        benzyl are optionally substituted with C₁-C₆-alkyl, halogen, or        C₁-C₆-alkoxy;        -   R^(e) at each occurrence, is independently hydrogen,            C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, cycloalkyl,            cycloalkyl-C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; wherein said            aryl, the aryl of aryl-C₁-C₆-alkyl, the cycloalkyl, and the            cycloalkyl of cycloalkyl-C₁-C₆-alkyl are independently            unsubstituted or substituted with 1, 2 3, 4, or 5            substituents independently selected from the group            consisting of C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen;            and        -   R^(f) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to voltage-gated sodium channel (and particularlyNa_(v)1.7 and Na_(v)1.8) activity.

Yet another aspect of the invention relates to a method of selectivelyblocking voltage-gated sodium channels (e.g., Na_(v)1.7 and Na_(v)1.8channels). The method is useful for treating, or preventing conditionsand disorders related to blocking voltage-gated sodium channels inmammals. More particularly, the method is useful for treating orpreventing conditions and disorders related to pain, neuropathy,inflammation, auto-immune disease, fibrosis, chronic kidney disease, andcancer. Accordingly, the compounds and compositions of the invention areuseful as a medicament for treating or preventing voltage-gated sodiumchannel modulated disease.

The compounds, compositions comprising the compounds, methods for makingthe compounds, and methods for treating or preventing conditions anddisorders by administering the compounds are further described herein.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I) are disclosed in this invention

wherein R¹, R² and R³ are as defined above in the Summary. Compositionscomprising such compounds and methods for treating conditions anddisorders using such compounds and compositions are also disclosed.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the invention or any other formulae herein. Definition of avariable on each occurrence is independent of its definition at anotheroccurrence. Further, combinations of substituents are permissible onlyif such combinations result in stable compounds. Stable compounds arecompounds which can be isolated from a reaction mixture.

Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. Representative examples of alkenylinclude, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 2 to 10 carbon atoms containing atleast one double bond. Representative examples of alkenylene include,but are not limited to, —CH═CH—, —CH═CH₂CH₂—, and —CH═C(CH₃)CH₂—.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxyimino” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an imino group,as defined herein. Representative examples of alkoxyimino include, butare not limited to, ethoxy(imino) (i.e., CH₃CH₂O—N═) and methoxy(imino)(i.e., CH₃O—N═)

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁-C₆-alkyl” means a straight or branched chain hydrocarboncontaining from 1 to 6 carbon atoms. The term “C₁-C₃-alkyl” means astraight or branched chain hydrocarbon containing from 1 to 3 carbonatoms. Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain hydrocarbon containing from 1 to 10 carbon atoms.Representative examples of alkylene include, but are not limited to,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the aryl groups include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thebicyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the bicyclic ring system. The aryl groupsof the present invention can be unsubstituted or substituted.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein.

Representative examples of cyanoalkyl include, but are not limited to,cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl” or “cycloalkene” as used herein, means amonocyclic or a bicyclic hydrocarbon ring system. The monocycliccycloalkenyl has four-, five-, six-, seven- or eight carbon atoms andzero heteroatoms. The four-membered ring systems have one double bond,the five- or six-membered ring systems have one or two double bonds, andthe seven- or eight-membered ring systems have one, two or three doublebonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl. The bicyclic cycloalkenylis a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, ora monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group, or abridged monocyclic ring system in which two non-adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge containing one,two, three, or four carbon atoms. Representative examples of thebicyclic cycloalkenyl groups include, but are not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems, and can be unsubstituted orsubstituted.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, a tricyclic, or a spirocyclic cycloalkyl. Themonocyclic cycloalkyl is a carbocyclic ring system containing three toeight carbon atoms, zero heteroatoms and zero double bonds.

Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicycliccycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkylring, or a bridged monocyclic ring system in which two non-adjacentcarbon atoms of the monocyclic ring are linked by an alkylene bridgecontaining one, two, three, or four carbon atoms. Representativeexamples of bicyclic ring systems include, but are not limited to,bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.

Tricyclic cycloalkyls are exemplified by a bicyclic cycloalkyl fused toa monocyclic cycloalkyl, or a bicyclic cycloalkyl in which twonon-adjacent carbon atoms of the ring systems are linked by an alkylenebridge of 1, 2, 3, or 4 carbon atoms. Representative examples oftricyclic-ring systems include, but are not limited to,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). Themonocyclic, bicyclic, and tricyclic cycloalkyls can be unsubstituted orsubstituted, and are attached to the parent molecular moiety through anysubstitutable atom contained within the ring system. Spirocycliccycloalkyl is exemplified by a monocyclic or a bicyclic cycloalkyl,wherein two of the substituents on the same carbon atom of the ring,together with said carbon atom, form a 4-, 5-, or 6-membered monocycliccycloalkyl. An example of a spirocyclic cycloalkyl is spiro[2.5]octane.The spirocyclic cycloalkyl groups of the present invention can beappended to the parent molecular moiety through any substitutable carbonatom of the groups.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl groupappended to the parent molecular moiety through an alkyl group, asdefined herein.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by halogen. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or abicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive-membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen orsulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. Thebicyclic heteroaryl consists of a monocyclic heteroaryl fused to aphenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, ora monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or amonocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclicheteroaryl fused to a monocyclic heterocycle.

Representative examples of bicyclic heteroaryl groups include, but arenot limited to, benzofuranyl, benzothienyl, benzoxazolyl,benzimidazolyl, benzoxadiazolyl, 6,7-dihydro-1,3-benzothiazolyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl,naphthyridinyl, pyridoimidazolyl, quinolinyl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups of the present invention can be substituted or unsubstituted andare connected to the parent molecular moiety through any carbon atom orany nitrogen atom contained within the ring systems.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, a tricyclic heterocycle,or a spirocyclic heterocycle. The monocyclic heterocycle is a three-,four-, five-, six-, seven-, or eight-membered ring containing at leastone heteroatom independently selected from the group consisting of O, N,and S. The three- or four-membered ring contains zero or one doublebond, and one heteroatom selected from the group consisting of O, N, andS. The five-membered ring contains zero or one double bond and one, twoor three heteroatoms selected from the group consisting of O, N and S.The six-membered ring contains zero, one or two double bonds and one,two, or three heteroatoms selected from the group consisting of O, N,and S. The seven- and eight-membered rings contains zero, one, two, orthree double bonds and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a bridged monocyclicheterocycle ring system in which two non-adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non-adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane), andoctahydro-1H-4,7-epiminoisoindole. The spirocyclic heterocycles areexemplified by a monocyclic heterocycle as defined herein wherein onecarbon atom of the monocyclic heterocycle is bridged by two ends of analkylene chain. In the spirocyclic heterocycle, one or more carbon atomsin the bridging alkylene chain may be replaced with a heteroatom.Examples of spirocyclic heterocycles include, but are not limited to,4,7-diazaspiro[2.5]octane, 2-oxa-6-azaspiro[3.3]heptane,2,6-diazaspiro[3.3]heptane, 2-oxa-5,8-diazaspiro[3.5]nonane,2,7-diazaspiro[3.5]nonane, 1,4-dioxa-8-azaspiro[4.5]decane,1,6-diazaspiro[3.3]heptane, 1-azaspiro[4.4]nonane,7-azaspiro[3.5]nonane, 1,4-dioxa-7-azaspiro[4.4]nonane,5,8-diazaspiro[3.5]nonane, 5,8-dioxa-2-azaspiro[3.4]octane,2-oxa-6-azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane,6-oxa-2-azaspiro[3.4]octane, 6-oxa-2-azaspiro[3.5]nonane, and7-oxa-2-azaspiro[3.5]nonane. The monocyclic, bicyclic, tricyclic, andspirocyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heteroatom” as used herein, means a nitrogen, oxygen, orsulfur atom.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.

The term “imino” as defined herein means a (═NH)— group.

The term “nitro” as used herein means a —NO₂ group.

The term “oxo” as used herein means (═O).

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicatedby the prefix “C_(x)-C_(y)-”, wherein x is the minimum and y is themaximum number of carbon atoms in the substituent. Thus, for example,“C₁-C₆-alkyl” refers to an alkyl substituent containing from 1 to 6carbon atoms. Illustrating further, C₃-C₆-cycloalkyl means a saturatedhydrocarbyl ring containing from 3 to 6 carbon ring atoms.

As used herein, the term “radiolabel” refers to a compound of theinvention in which at least one of the atoms is a radioactive atom orradioactive isotope, wherein the radioactive atom or isotopespontaneously emits gamma rays or energetic particles, for example alphaparticles or beta particles, or positrons. Examples of such radioactiveatoms include, but are not limited to, ³H (tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F,³⁵S, ¹²³I, and ¹²⁵I.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described in theSummary.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values can be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In one embodiment, R¹ is selected from the group consisting of phenyland monocyclic 5- or 6-membered heteroaryl, wherein the phenyl or 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —NO₂, —OR^(1a),—OC(O)R^(1a), —OC(O)N(R^(b))(R^(3a)), —SR^(1a), —S(O)R^(2a),—S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —C(O)OR^(1a),—C(O)N(R^(b))(R^(3a)), —N(R^(b))(R^(3a)), —N(R^(a))C(O)R^(1a),—N(R^(a))C(O)O(R^(1a)), —N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—NO₂, —N(R^(b))S(O)₂(R^(2a)),—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(a))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),(CR^(4a)R^(5a))_(m)—N(R^(b))S(O)₂(R^(2a)), cyano-C₁-C₆-alkyl, andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) andR^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, halogen, C₁-C₆-alkyl,or halo-C₁-C₆-alkyl; and m, at each occurrence, is independently 1, 2,3, 4, or 5.

In one embodiment, R¹ is selected from the group consisting of phenyland monocyclic 5- or 6-membered heteroaryl, wherein the phenyl or 5- or6-membered heteroaryl is unsubstituted or substituted with 1 or 2substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(a) and R^(b), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; R^(1a)and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; and m,at each occurrence, is independently 1 or 2.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano,—NO₂, —OR^(1a), —OC(O)R^(1a), —OC(O)N(R^(b))(R^(3a)), —SR^(1a),—S(O)R^(2a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—C(O)OR^(1a), —C(O)N(R^(b))(R^(3a)), —N(R^(b))(R^(3a)),—N(R^(a))C(O)R^(1a), —N(R^(a))C(O)O(R^(1a)),—N(R^(a))C(O)N(R^(b))(R^(3a)), —(CR^(4a)R^(5a))_(m)—NO₂,—N(R^(b))S(O)₂(R^(2a)), —(CR^(4a)R^(5a))_(m)—OR^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(a))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))S(O)₂(R^(2a)), cyano-C₁-C₆-alkyl, andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) andR^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, halogen, C₁-C₆-alkyl,or halo-C₁-C₆-alkyl; and m, at each occurrence, is independently 1, 2,3, 4, or 5.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1 or 2 substituents selected from the group consistingof C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(a) and R^(b), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; R^(1a)and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; and m,at each occurrence, is independently 1 or 2.

In one embodiment, R¹ is monocyclic 5- or 6-membered heteroaryl, whereinthe 5- or 6-membered heteroaryl is unsubstituted or substituted with 1,2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —NO₂,—OR^(1a), —OC(O)R^(1a), —OC(O)N(R^(b))(R^(3a)), —SR^(1a), —S(O)R^(2a),—S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —C(O)OR^(a),—C(O)N(R^(b))(R^(3a)), N(R^(b))(R^(3a)), —N(R^(a))C(O)R^(1a),—N(R^(a))C(O)O(R^(1a)), —N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—NO₂, —N(R^(b))S(O)₂(R^(2a)),—(CR^(4a)R^(5a))_(m)—OR^(1a), —(CR^(4a)R^(5a))_(m)—OC(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OC(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—SR^(1a), —(CR^(4a)R^(5a))_(m)—S(O)R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂R^(2a),—(CR^(4a)R^(5a))_(m)—S(O)₂N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—C(O)OR^(1a),—(CR^(4a)R^(5a))_(m)—C(O)N(R^(a))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)O(R^(1a)),—(CR^(4a)R^(5a))_(m)—N(R^(a))C(O)N(R^(b))(R^(3a)),—(CR^(4a)R^(5a))_(m)—N(R^(b))S(O)₂(R^(2a)), cyano-C₁-C₆-alkyl, andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) andR^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, halogen, C₁-C₆-alkyl,or halo-C₁-C₆-alkyl; and m, at each occurrence, is independently 1, 2,3, 4, or 5.

In one embodiment, R¹ is monocyclic 5- or 6-membered heteroaryl, whereinthe 5- or 6-membered heteroaryl is unsubstituted or substituted with 1or 2 substituents selected from the group consisting of C₁-C₆-alkyl,halogen, cyano, —OR^(1a), —S(O)₂R^(2a), —C(O)R^(1a),—(CR^(4a)R^(a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(a) and R^(b), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; R^(1a)and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; and m,at each occurrence, is independently 1 or 2.

In one embodiment, R² is selected from the group consisting of hydrogen,C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, and -G², wherein -G² is asdefined in the Summary.

In one embodiment, R² is hydrogen.

In one embodiment, R² is C₁-C₆-alkyl.

In one embodiment, R² is selected from the group consisting ofC₁-C₆-alkoxy-C₁-C₆-alkyl and -G², wherein -G² is as defined in theSummary.

In one embodiment, R³ is selected from the group consisting of hydrogen,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(CR^(4b)R^(5b))_(n)—NO₂,—(CR^(4b)R^(5b))_(n)—OR^(1b), —CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]2,—(CR^(4b)R^(5b))_(n)—OC(O)R^(1b),—(CR^(4b)R^(5b))_(n)—OC(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—SR^(1b), —(CR^(4b)R^(5b))_(n)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)R^(1b), —(CR^(4b)R^(5b))_(n)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))C(O)N(R^(b))((CR^(4b)R^(5b))_(n)—OR^(1b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G⁴),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G³), (CR^(4b)R^(5b))_(n)—C(O)G⁴,—(CR^(4b)R^(5b))_(n)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—N(R^(b))(G³),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(n)—N(R^(b))S(O)₂R^(2b), —S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)N(R^(b))(R^(3b)), -G²,—(CR^(4b)R^(5b))_(n)-G⁴, -G²-G⁶, -G¹-(CR^(4b)R^(5b))_(n)-G³,—CH[C(O)N(R^(b))(R^(3b))][—(CR^(4b)R^(5b))_(n)-G³], cyano-C₁-C₆-alkyl,and halo-C₁-C₆-alkyl; R^(1b) and R^(3b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2b), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4b) and R^(5b), at each occurrence, are each independently hydrogen,halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; n, at each occurrence, isindependently 1, 2, 3, 4, or 5; G¹ and G³ are each independently aryl orheteroaryl; wherein G¹ and G³ are each independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano,halo-C₁-C₆-alkyl, halogen, nitro, —N(R^(c))₂, —N(R^(c))C(O)R^(c),—OR^(c), —C(O)R^(c), —C(O)OR^(c), —C(O)N(R^(c))₂, —SO₂R^(d), and—SO₂N(R^(c))₂; G², G⁴ and G⁶ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle; wherein G², G⁴ and G⁶ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,oxo, —N(R^(c))₂, —N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c), —C(O)OR^(c),—C(O)N(R^(c))₂, —SO₂R^(d), —SO₂N(R^(c))₂, and phenyl, wherein phenyl andthe phenyl ring of benzyl are optionally substituted with 1, 2, 3, or 4C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(c) at each occurrence, isindependently hydrogen, C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, cycloalkyl,cycloalkyl-C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; wherein said aryl, the arylof aryl-C₁-C₆-alkyl, the cycloalkyl, and the cycloalkyl ofcycloalkyl-C₁-C₆-alkyl are independently unsubstituted or substitutedwith 1, 2 3, 4, or 5 substituents independently selected from the groupconsisting of C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(d) isC₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R³ is selected from the group consisting of hydrogen,C₁-C₆-alkyl, C₂-C₆-alkenyl, —(CR^(4b)R^(5b))_(n)—OR^(1b),—CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]₂, —(CR^(4b)R^(5b))_(n)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))C(O)N(R^(b))(—(CR^(4b)R^(5b))_(n)—OR^(1b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G⁴),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G³), —(CR^(4b)R^(5b))_(n)—C(O)G⁴,—(CR^(4b)R^(5b))N(R^(b))(R^(3b)), —(CR^(4b)R^(5b))_(n)—N(R^(b))(G³),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)R^(1b), —S(O)₂R^(2b), -G²,—(CR^(4b)R^(5b))_(n)-G⁴, -G²- G⁶, -G¹, —(CR^(4b)R^(5b))_(n)-G³,—CH[C(O)N(R^(b))(R^(3b))][—(CR^(4b)R^(5b))_(n)-G³], cyano-C₁-C₆-alkyl,and halo-C₁-C₆-alkyl; R^(1b) and R^(3b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2b), ateach occurrence, is C₁-C₆-alkyl; R^(4b) and R^(5b), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; n, ateach occurrence, is independently 1, 2, 3, or 4; G¹ and G³ are eachindependently aryl or heteroaryl; wherein G¹ and G³ are eachindependently unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of C₁-C₆-alkyl and —OR^(c); G², G⁴and G⁶ are each independently 3-6-membered-cycloalkyl or4-10-membered-heterocycle; wherein G², G⁴ and G⁶ are each independentlyunsubstituted or substituted with 1, 2 or 3 substituents selected fromthe group consisting of C₁-C₆-alkyl, benzyl, hydroxy-C₁-C₆-alkyl,halogen, oxo, —OR^(c), and phenyl, wherein phenyl and the phenyl ring ofbenzyl are optionally substituted with 1, 2, 3, or 4 halogen, orC₁-C₆-alkoxy; and R^(c) at each occurrence, is independently hydrogen,C₁-C₆-alkyl, aryl, or halo-C₁-C₆-alkyl; wherein said aryl, isunsubstituted or substituted with 1, 2 3, 4, or 5 substituentsindependently selected from the group consisting of C₁-C₆-alkyl,halo-C₁-C₆-alkyl, and halogen.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 4-8-membered-monocylic heterocycle,6-11-membered-bicyclic heterocycle, 10-12-membered-tricyclicheterocycle, 7-11-membered-spirocyclic heterocycle or8-11-membered-bicyclic heteroaryl comprised of a monocyclic heterocyclefused to a monocyclic heteroaryl, wherein said 4-8-membered monocyclicheterocycle, said 6-11-membered-bicyclic heterocycle, said,10-12-membered-tricyclic heterocycle, said 7-11-membered-spirocyclicheterocycle and said 8-11-membered-bicyclic heteroaryl are unsubstitutedor substituted with 1, 2, 3, 4, or 5 substituents selected from thegroup consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen,cyano, —NO₂, —OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³,—OC(O)R^(1c), —OC(O)N(R^(b))(R^(3c)), —SR^(1c), —S(O)R^(2c),—S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—NO₂, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p) S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogen,halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, 3, 4, or 5; G¹¹ and G¹³ are each independentlyphenyl or 5-6-membered-heteroaryl; wherein G¹¹ and G¹³ are eachindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen, nitro, —N(R^(e))₂, —N(R^(e))C(O)R^(e),—OR^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), and—SO₂N(R^(e))₂; G¹² and G¹⁴ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,oxo, —N(R^(e))₂, —N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f), —OR^(e),—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), —SO₂N(R^(e))₂, andphenyl, wherein phenyl and the phenyl ring of benzyl are optionallysubstituted with C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(e) at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, aryl,aryl-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; wherein said aryl, the aryl of aryl-C₁-C₆-alkyl, thecycloalkyl, and the cycloalkyl of cycloalkyl-C₁-C₆-alkyl areindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 4-8-membered-monocylic heterocycle,6-11-membered-bicyclic heterocycle, 10-12-membered-tricyclicheterocycle, 7-11-membered-spirocyclic heterocycle or8-11-membered-bicyclic heteroaryl comprised of a monocyclic heterocyclefused to a monocyclic heteroaryl, wherein said 4-8-membered monocyclicheterocycle, said 6-11-membered-bicyclic heterocycle, said,10-12-membered-tricyclic heterocycle, said 7-11-membered-spirocyclicheterocycle and said 8-11-membered-bicyclic heteroaryl are unsubstitutedor substituted with 1, 2, 3 or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —NO₂, —OR^(1c),—O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —SR^(1c), —S(O)₂R^(2c),—S(O)₂G¹³, —S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)OR^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogenor C₁-C₆-alkyl; p, at each occurrence, is independently 1 or 2; G¹¹ andG¹³ are each independently phenyl or 5-6-membered-heteroaryl; whereinG¹¹ and G¹³ are each independently unsubstituted or substituted with 1or 2 substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹², and G¹⁴ are each independently 3-6-membered-cycloalkylor 4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of C₁-C₆-alkyl, halogen, oxo, and —N(R^(e))S(O)₂R^(f);R^(e) at each occurrence, is independently hydrogen or C₁-C₆-alkyl; andR^(f) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 4-8-membered-monocylic heterocycle is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano,—NO₂, —OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —OC(O)R^(1c),—OC(O)N(R^(b))(R^(3c)), —SR^(1c), —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³,—S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—NO₂, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogen,halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, 3, 4, or 5; and G¹³ are each independently phenyl or5-6-membered-heteroaryl; wherein G¹¹ and G¹³ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, nitro,—N(R^(e))₂, —N(R^(e))C(O)R^(e), —OR^(e), —C(O)R^(e), —C(O)OR^(e),—C(O)N(R^(e))₂, —SO₂R^(f), and —SO₂N(R^(e))₂; G¹², and G¹⁴ are eachindependently 3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,oxo, —N(R^(e))₂, —N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f), —OR^(e),—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), —SO₂N(R^(e))₂, andphenyl, wherein phenyl and the phenyl ring of benzyl are optionallysubstituted with C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(e) at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, aryl,aryl-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; wherein said aryl, the aryl of aryl-C₁-C₆-alkyl, thecycloalkyl, and the cycloalkyl of cycloalkyl-C₁-C₆-alkyl areindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 4-8-membered-monocylic heterocycle is unsubstituted orsubstituted with 1, 2, 3 or 4, substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1c),—O—(CR^(4c)R^(5c))_(p)OR^(1c), —OG¹³, —SR^(1c), —S(O)₂R^(2c), —S(O)₂G¹³,—S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹³,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C₁-C₆-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogenor C₁-C₆-alkyl; p, at each occurrence, is independently 1 or 2; G¹¹ andG¹³ are each independently phenyl or 5-6-membered-heteroaryl; whereinG¹¹ and G¹³ are each independently unsubstituted or substituted with 1or 2 substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹², and G¹⁴ are each independently 3-6-membered-cycloalkylor 4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of C₁-C₆-alkyl, halogen, oxo, and —N(R^(e))S(O)₂R^(f);R^(e) at each occurrence, is independently hydrogen or C₁-C₆-alkyl; andR^(f) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 6-11-membered-bicyclic heterocycle, wherein said6-11-membered-bicyclic heterocycle, is unsubstituted or substituted with1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —NO₂,—OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —OC(O)R^(1c),—OC(O)N(R^(b))(R^(3c)), —SR^(1c), —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³,—S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—NO₂, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogen,halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, 3, 4, or 5; G¹¹ and G¹³ are each independentlyphenyl or 5-6-membered-heteroaryl; wherein G¹¹ and G¹³ are eachindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen, nitro, —N(R^(e))₂, —N(R^(e))C(O)R^(e),—OR^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), and—SO₂N(R^(e))₂; G¹², and G¹⁴ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,oxo, —N(R^(e))₂, —N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f), —OR^(e),—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), —SO₂N(R^(e))₂, andphenyl, wherein phenyl and the phenyl ring of benzyl are optionallysubstituted with C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(e) at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, aryl,aryl-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; wherein said aryl, the aryl of aryl-C₁-C₆-alkyl, thecycloalkyl, and the cycloalkyl of cycloalkyl-C₁-C₆-alkyl areindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 6-11-membered-bicyclic heterocycle, wherein said6-11-membered-bicyclic heterocycle, is unsubstituted or substituted with1, 2, 3 or 4, substituents selected from the group consisting ofC₁-C₆-alkyl, halogen, cyano, —OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c),—OG¹³, —SR^(1c), —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴,—S(O)₂N(R^(b))(R^(3c)), —S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴, —C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c),—C(O)N(R^(b))(R^(3c)), —N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c),—N(R^(a))C(O)G¹⁴, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogenor C₁-C₆-alkyl; p, at each occurrence, is independently 1 or 2; G¹¹ andG¹³ are each independently phenyl or 5-6-membered-heteroaryl; whereinG¹¹ and G¹³ are each independently unsubstituted or substituted with 1or 2 substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹² and G¹⁴ are each independently 3-6-membered-cycloalkylor 4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of C₁-C₆-alkyl, halogen, oxo, and —N(R^(e))S(O)₂R^(f);R^(e) at each occurrence, is independently hydrogen or C₁-C₆-alkyl; andR^(f) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 10-12-membered-tricyclic heterocycle or7-11-membered-spirocyclic heterocycle, wherein said10-12-membered-tricyclic heterocycle and said 7-11-membered-spirocyclicheterocycle are unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —NO₂, —OR^(1c),—O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —OC(O)R^(1c),—OC(O)N(R^(b))(R^(3c)), —SR^(1c), —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³,—S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)), (O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴, —C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c),—C(O)N(R^(b))(R^(3c)), —N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c),—N(R^(a))C(O)G¹⁴, —N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—NO₂, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), —(CR^(4c)R^(5c))_(p)-G¹³,—(CR^(4c)R^(5c))_(p)—OG¹³, -G¹², —(CR^(4c)R^(5c))_(p)- G¹⁴,cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino and halo-C₁-C₆-alkyl; R^(1c)and R^(3c), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4c) and R^(5c), ateach occurrence, are each independently hydrogen, halogen, C₁-C₆-alkyl,or halo-C₁-C₆-alkyl; p, at each occurrence, is independently 1, 2, 3, 4,or 5; G¹⁴ and G¹³ are each independently phenyl or5-6-membered-heteroaryl; wherein G¹⁴ and G¹³ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, nitro,—N(R^(e))₂, —N(R^(e))C(O)R^(e), —OR^(e), —C(O)R^(e), —C(O)OR^(e),—C(O)N(R^(e))₂, —SO₂R^(f), and —SO₂N(R^(e))₂; G¹¹, and G¹⁴ are eachindependently 3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,oxo, —N(R^(e))₂, —N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f), —OR^(e),—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), —SO₂N(R^(e))₂, andphenyl, wherein phenyl and the phenyl ring of benzyl are optionallysubstituted with C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(e) at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, aryl,aryl-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; wherein said aryl, the aryl of aryl-C₁-C₆-alkyl, thecycloalkyl, and the cycloalkyl of cycloalkyl-C₁-C₆-alkyl areindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form a 10-12-membered-tricyclic heterocycle or7-11-membered-spirocyclic heterocycle, wherein said10-12-membered-tricyclic heterocycle and said 7-11-membered-spirocyclicheterocycle are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —SR^(1c),—S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogenor C₁-C₆-alkyl; p, at each occurrence, is independently 1 or 2; G¹¹ andG¹³ are each independently phenyl or 5-6-membered-heteroaryl; whereinG¹¹ and G¹³ are each independently unsubstituted or substituted with 1or 2 substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹², and G¹⁴ are each independently 3-6-membered-cycloalkylor 4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of C₁-C₆-alkyl, halogen, oxo, and —N(R^(e))S(O)₂R^(f);R^(e) at each occurrence, is independently hydrogen or C₁-C₆-alkyl; andR^(f) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form an 8-11-membered-bicyclic heteroaryl comprised of amonocyclic heterocycle fused to a monocyclic heteroaryl, wherein8-11-membered-bicyclic heteroaryl is unsubstituted or substituted with1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —NO₂,—OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —OC(O)R^(1c),—OC(O)N(R^(b))(R^(3c)), —SR^(1c), —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³,—S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))O(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—NO₂, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogen,halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, 3, 4, or 5; G¹¹ and G¹³ are each independentlyphenyl or 5-6-membered-heteroaryl; wherein G¹¹ and G¹³ are eachindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen, nitro, —N(R^(e))₂, —N(R^(e))C(O)R^(e),—OR^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), and—SO₂N(R^(e))₂; G¹² and G¹⁴ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, nitro,oxo, —N(R^(e))₂, —N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f), —OR^(e),—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), —SO₂N(R^(e))₂, andphenyl, wherein phenyl and the phenyl ring of benzyl are optionallysubstituted with C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(e) at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, aryl,aryl-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; wherein said aryl, the aryl of aryl-C₁-C₆-alkyl, thecycloalkyl, and the cycloalkyl of cycloalkyl-C₁-C₆-alkyl areindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R², R³ and the nitrogen atom to which they areattached form an 8-11-membered-bicyclic heteroaryl comprised of amonocyclic heterocycle fused to a monocyclic heteroaryl, wherein8-11-membered-bicyclic heteroaryl is unsubstituted or substituted with1, 2, 3 or 4 substituents selected from the group consisting ofC₁-C₆-alkyl, halogen, cyano, —OR^(1c), —O—(CR^(4c)R^(5c))_(p)—OR^(1c),—OG¹³, —SR^(1c), —S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴,—S(O)₂N(R^(b))(R^(3c)), —S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴, —C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c),—C(O)N(R^(b))(R^(3c)), —N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c),—N(R^(a))C(O)G¹⁴, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogenor C₁-C₆-alkyl; p, at each occurrence, is independently 1 or 2; G¹¹ andG¹³ are each independently phenyl or 5-6-membered-heteroaryl; whereinG¹¹ and G¹³ are each independently unsubstituted or substituted with 1or 2 substituents selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹² and G¹⁴ are each independently 3-6-membered-cycloalkylor 4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of C₁-C₆-alkyl, halogen, oxo, and —N(R^(e))S(O)₂R^(f);R^(e) at each occurrence, is independently hydrogen or C₁-C₆-alkyl; andR^(f) is C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; and m, at eachoccurrence, is independently 1, 2, or 3.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; and m, at eachoccurrence, is independently 1, 2, or 3; R² is selected from the groupconsisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, and -G²;R³ is selected from the group consisting of hydrogen, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(CR^(4b)R^(5b))_(n)—OR^(1b),—CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]2, —(CR^(4b)R^(5b))_(n)—SR^(1b),—(CR^(4b)R^(5b))_(n)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)R^(1b), —(CR^(4b)R^(5b))_(n)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(—(CR^(4b)R^(5b))_(n)—OR^(1b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G⁴),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G³), —(CR^(4b)R^(5b))_(n)—C(O)G⁴,—(CR^(4b)R^(5b))_(n)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—N(R^(b))(G³),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(n)—N(R^(b))S(O)₂R^(2b), —S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)N(R^(b))(R^(3b)), -G²,—(CR^(4b)R^(5b))_(n)-G⁴, -G²-G⁶, -G¹, —(CR^(4b)R^(5b))_(n)-G³,—CH[C(O)N(R^(b))(R^(3b))][—(CR^(4b)R^(5b))_(n)-G³], cyano-C₁-C₆-alkyl,and halo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1b) and R^(3b), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2b), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4b) and R^(5b), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; n, at each occurrence, is independently 1, 2, 3, 4, or5; G¹ and G³ are each independently aryl or heteroaryl; wherein G¹ andG³ are each independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, halo-C₁-C₆-alkyl, halogen, nitro,—N(R^(c))₂, —N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c), —C(O)OR^(c),—C(O)N(R^(c))₂, —SO₂R^(d), and —SO₂N(R^(c))₂; G², G⁴ and G⁶ are eachindependently 3-6-membered-cycloalkyl or 4-10-membered-heterocycle;wherein G², G⁴ and G⁶ are each independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, benzyl, cyano,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo, —N(R^(c))₂,—N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c), —C(O)OR^(c), —C(O)N(R^(c))₂,—SO₂R^(d), —SO₂N(R^(c))₂, and phenyl, wherein phenyl and the phenyl ringof benzyl are optionally substituted with 1, 2, 3, or 4 C₁-C₆-alkyl,halogen, or C₁-C₆-alkoxy; R^(c) at each occurrence, is independentlyhydrogen, C₁-C₆-alkyl, aryl, or halo-C₁-C₆-alkyl; wherein said aryl isindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(d) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C1-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R² is selected from the groupconsisting of hydrogen and C₁-C₆-alkyl; R³ is selected from the groupconsisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,—(CR^(4b)R^(5b))_(n)—OR^(1b), —CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]₂,—(CR^(4b)R^(5b))_(n)—SR^(1b), —(CR^(4b)R^(5b))_(n)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)R^(1b), —(CR^(4b)R^(5b))_(n)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—N(R^(b))(R^(3b)), —S(O)₂R^(2b), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1b) and R^(3b), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2b), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4b) and R^(5b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; and n, at eachoccurrence, is independently 1, 2, 3, or 4. In one embodiment, R¹ isphenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3,or 4 substituents selected from the group consisting of C₁-C₆-alkyl,halogen, cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)),—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b),at each occurrence, is independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4a) and R^(5a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at each occurrence, isindependently 1, 2, or 3; R² is selected from the group consisting ofhydrogen and C₁-C₆-alkyl; R³ is selected from the group consisting of-G¹ and —(CR^(4b)R^(5b))_(n)-G³; R^(4b) and R^(5b), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; n, ateach occurrence, is independently 1, 2, 3, 4, or 5; G¹ and G³ are eachindependently aryl or heteroaryl; wherein G¹ and G³ are eachindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, halo-C₁-C₆-alkyl, halogen, and —OR^(c); and R^(c) at eachoccurrence, is independently C₁-C₆-alkyl, aryl, or halo-C₁-C₆-alkyl;wherein said aryl is independently unsubstituted or substituted with 1,2 3, 4, or 5 substituents independently selected from the groupconsisting of C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen. In oneembodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R² is selected from the groupconsisting of hydrogen and C₁-C₆-alkyl; R³ is selected from the groupconsisting of -G² and —(CR^(4b)R^(5b))_(n)-G⁴; R^(4b) and R^(5b), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; n is 1, 2, 3, 4, or 5; G² and G⁴ are eachindependently 3-6-membered-cycloalkyl or 4-10-membered-heterocycle;wherein G² and G⁴ are each independently unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, benzyl, cyano, halo-C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, halogen, oxo, —OR^(c), and phenyl, wherein phenyland the phenyl ring of benzyl are optionally substituted with 1, 2, 3,or 4 C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; and R^(c) at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl or halo-C₁-C₆-alkyl.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R², R³ and the nitrogen atom towhich they are attached form a 4-8-membered-monocylic heterocycle,6-11-membered-bicyclic heterocycle, 10-12-membered-tricyclicheterocycle, 7-11-membered-spirocyclic heterocycle or8-11-membered-bicyclic heteroaryl comprised of a 5-7-membered-monocyclicheterocycle fused to a 5-6-membered-monocyclic heteroaryl, wherein said4-8-membered monocyclic heterocycle, said 6-11-membered-bicyclicheterocycle, said, 10-12-membered-tricyclic heterocycle, said7-11-membered-spirocyclic heterocycle and said 8-11-membered-bicyclicheteroaryl are unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —OR^(1c),—O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —SR^(1c), —S(O)R^(2c),—S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1c) andR^(3c) at each occurrence, are each independently hydrogen, C₁-C₆-alkyl,or halo-C₁-C₆-alkyl; R^(2c), at each occurrence, is independentlyC₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4c) and R^(5c), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; p, ateach occurrence, is independently 1, 2, 3, 4, or 5; G¹¹ and G¹³ are eachindependently phenyl or 5-6-membered-heteroaryl; wherein G¹¹ and G¹³ areeach independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, C₁-C₆-alkoxy-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e), and —OR^(e); G¹², and G¹⁴are each independently 3-6-membered-cycloalkyl,3-6-membered-cycloalkenyl, or 4-10-membered-heterocycle, wherein G¹² andG¹⁴ are each independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, benzyl, cyano, halo-C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, halogen, oxo, —N(R^(e))C(O)R^(e),—N(R^(e))S(O)₂R^(f), —OR^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))₂,—SO₂R^(f), —SO₂N(R^(e))₂, and phenyl, wherein phenyl and the phenyl ringof benzyl are optionally substituted with C₁-C₆-alkyl, halogen, orC₁-C₆-alkoxy; R^(e) at each occurrence, is independently hydrogen,C₁-C₆-alkyl, aryl or halo-C₁-C₆-alkyl; wherein said aryl, isindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R², R³ and the nitrogen atom towhich they are attached form a 4-8-membered monocyclic heterocycle,wherein said 4-8-membered monocyclic heterocycle is unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1c), —S(O)₂R^(2c),—S(O)₂N(R^(b))(R^(3c)), —C(O)R^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),-G¹², —(CR^(4c)R^(5c))_(p)-G¹⁴, oxo, and halo-C₁-C₆-alkyl; R^(a) andR^(b), at each occurrence, are each independently hydrogen, C₁-C₆-alkyl,or halo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4c) and R^(5c), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, 3, 4, or 5; and G¹² and G¹⁴ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, cyano, halo-C₁-C₆-alkyl,halogen, and oxo.

In one embodiment, R¹ is selected from the group consisting of4-cyanophenyl and 4-acetylphenyl; R², R³ and the nitrogen atom to whichthey are attached form an azetidine, pyrrolidine or piperazine, whereinsaid azetidine, pyrrolidine or piperazine is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, —OR^(1c),—(CR^(4c)R^(5c))_(p)—OR^(1c), -G¹², and halo-C₁-C₆-alkyl; R^(1c), ateach occurrence, is each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; R^(4c) and R^(5c), at each occurrence, are eachindependently hydrogen or C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, or 3; and G¹², at each occurrence, is eachindependently 5-6-membered-heterocycle, wherein G¹² is eachindependently unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of C₁-C₆-alkyl, halogen, or oxo.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R², R³ and the nitrogen atom towhich they are attached form a 6-11-membered-bicyclic heterocycle,10-12-membered-tricyclic heterocycle, or 7-11-membered-spirocyclicheterocycle, wherein said 6-11-membered-bicyclic heterocycle, said,10-12-membered-tricyclic heterocycle, and said 7-11-membered-spirocyclicheterocycle are unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1c), —S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴,—S(O)₂N(R^(b))(R^(3c)), —S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴, —C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c),—C(O)N(R^(b))(R^(3c)), —N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c),—N(R^(a))C(O)G¹⁴, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1c) andR^(3c), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4c) and R^(5c), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; p, at each occurrence, is independently 1, 2, 3, 4, or5; G¹¹ and G¹³ are each independently phenyl or 5-6-membered-heteroaryl;wherein G¹¹ and G¹³ are each independently unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen,—N(R^(e))C(O)R^(e), and —OR^(e); G¹², and G¹⁴ are each independently3-6-membered-cycloalkyl or 4-10-membered-heterocycle, wherein G¹² andG¹⁴ are each independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₆-alkyl,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo,—N(R^(e))S(O)₂R^(e), and —OR^(e); and R^(e) at each occurrence, isindependently hydrogen, C₁-C₆-alkyl, aryl or halo-C₁-C₆-alkyl; whereinsaid aryl, is independently unsubstituted or substituted with 1, 2 3, 4,or 5 substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen.

In one embodiment, R¹ is phenyl, wherein the phenyl is unsubstituted orsubstituted with 1, 2, 3, or 4 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R², R³ and the nitrogen atom towhich they are attached form a 8-11-membered-bicyclic heteroarylcomprised of a 5-7-membered-monocyclic heterocycle fused to a5-6-membered-monocyclic heteroaryl, wherein said 8-11-membered-bicyclicheteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1c), —S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴,—S(O)₂N(R^(b))(R^(3c)), —S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴, —C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c),—C(O)N(R^(b))(R^(3c)), —N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c),—N(R^(a))C(O)G¹⁴, —N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c), —(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(ic) andR^(3c), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4c) and R^(5c), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; p, at each occurrence, is independently 1, 2, 3, 4, or5; G¹¹ and G¹³ are each independently phenyl or 5-6-membered-heteroaryl;wherein G¹¹ and G¹³ are each independently unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen,—N(R^(e))C(O)R^(e), and —OR^(e); G¹², and G¹⁴ are each independently3-6-membered-cycloalkyl or 4-10-membered-heterocycle, wherein G¹² andG¹⁴ are each independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₆-alkyl,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo,—N(R^(e))S(O)₂R^(f), and —OR^(e); R^(e) at each occurrence, isindependently hydrogen, C₁-C₆-alkyl, aryl or halo-C₁-C₆-alkyl; whereinsaid aryl, is independently unsubstituted or substituted with 1, 2 3, 4,or 5 substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; and m, at each occurrence, is independently 1, 2, or3. In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5-or 6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3,or 4 substituents selected from the group consisting of C₁-C₆-alkyl,halogen, cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)),—C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b),at each occurrence, is independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), ateach occurrence, is independently C₁-C₆-alkyl or halo-C₁-C₆-alkyl;R^(4a) and R^(5a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at each occurrence, isindependently 1, 2, or 3; R² is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, and -G²; R³ is selectedfrom the group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, —(CR^(4b)R^(5b))_(n)—OR^(1b),—CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]₂, —(CR^(4b)R^(5b))_(n)—SR^(1b),—(CR^(4b)R^(5b))_(n)—S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)R^(1b), —(CR^(4b)R^(5b))_(n)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(—(CR^(4b)R^(5b))_(n)—OR^(1b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G⁴),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G³), —(CR^(4b)R^(5b))_(n)—C(O)G⁴,—(CR^(4b)R^(5b))_(n)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—N(R^(b))(G³),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(n)—N(R^(b))S(O)₂R^(2b), —S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)N(R^(b))(R^(3b)), -G²,—(CR^(4b)R^(5b))_(n)-G⁴, -G²-G⁶, -G¹, —(CR^(4b)R^(5b))_(n)-G³,—CH[C(O)N(R^(b))(R^(3b))][—(CR^(4b)R^(5b))_(n)-G³], cyano-C₁-C₆-alkyl,and halo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1b) andR^(3b), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2b), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4b) and R^(5b), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; n, at each occurrence, is independently 1, 2, 3, 4, or5; G¹ and G³ are each independently aryl or heteroaryl; wherein G¹ andG³ are each independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano, halo-C₁-C₆-alkyl, halogen, nitro,—N(R^(c))₂, —N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c), —C(O)OR^(c),—C(O)N(R^(c))₂, —SO₂R^(d), and —SO₂N(R^(c))₂; G², G⁴ and G⁶ are eachindependently 3-6-membered-cycloalkyl or 4-10-membered-heterocycle;wherein G², G⁴ and G⁶ are each independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, benzyl, cyano,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo, —N(R^(c))₂,—N(R^(c))C(O)R^(c), —OR^(c), —C(O)R^(c), —C(O)OR^(c), —C(O)N(R^(c))₂,—SO₂R^(d), —SO₂N(R^(c))₂, and phenyl, wherein phenyl and the phenyl ringof benzyl are optionally substituted with 1, 2, 3, or 4 C₁-C₆-alkyl,halogen, or C₁-C₆-alkoxy; R^(c) at each occurrence, is independentlyhydrogen, C₁-C₆-alkyl, aryl, or halo-C₁-C₆-alkyl; wherein said aryl isindependently unsubstituted or substituted with 1, 2 3, 4, or 5substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(d) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl. In one embodiment, R¹ is 5- or 6-membered heteroaryl,wherein the 5- or 6-membered heteroaryl is unsubstituted or substitutedwith 1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₆-alkyl, halogen, cyano, —OR^(1a), —S(O)₂R^(2a),—S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a), —(CR^(4a)R^(5a))_(m)—OR^(1a), andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1a) and R^(3a), at each occurrence,are each independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2a), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; m, at eachoccurrence, is independently 1, 2, or 3; R² is selected from the groupconsisting of hydrogen, C₁-C₆-alkyl, and C₁-C₆-alkoxy-C₁-C₆-alkyl; R³ isselected from the group consisting of hydrogen, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, —(CR^(4b)R^(5b))_(n)—OR^(1b),—CH[(CR^(4b)R^(5b))_(n)—OR^(1b)]₂, —(CR^(4b)R^(5b))_(n)—SR^(1b),—(CR^(4b)R^(5b))_(n-)S(O)₂R^(1b),—(CR^(4b)R^(5b))_(n)—S(O)₂N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)R^(1b), —(CR^(4b)R^(5b))_(n)—C(O)OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(—(CR^(4b)R^(5b))_(n)—OR^(1b)),—(CR^(4b)R^(5b))_(n)—N(R^(b))(R^(3b)),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)R^(1b),—(CR^(4b)R^(5b))_(n)—N(R^(b))S(O)₂R^(2b), —S(O)₂R^(2b),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)O(R^(1b)),—(CR^(4b)R^(5b))_(n)—N(R^(a))C(O)N(R^(b))(R^(3b)), cyano-C₁-C₆-alkyl,and halo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1b) andR^(3b), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2b), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4b) and R^(5b), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; and n, at each occurrence, is independently 1, 2, 3,4, or 5.

In one embodiment, R¹ is selected from the group consisting of5-(trifluoromethyl)pyridin-2-yl, 5-(difluoromethyl)pyridin-2-yl, and6-(trifluoromethyl)pyridin-3-yl; R² is hydrogen; R³ is selected from thegroup consisting of —(CR^(4b)R^(5b))_(n)—OR^(1b),—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(R^(3b)), and halo-C₁-C₆-alkyl; R^(b)is hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1b) and R^(3b), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; R^(4b)and R^(5b), at each occurrence, are each independently hydrogen orC₁-C₆-alkyl; and n, at each occurrence, is independently 1, 2, 3 or 4.In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; m, at each occurrence, is independently 1, 2, or 3; R²is selected from the group consisting of hydrogen and C₁-C₆-alkyl; R³ isselected from the group consisting of—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G³),—(CR^(4b)R^(5b))_(n)—N(R^(b))(G³), -G¹, —(CR^(4b)R^(5b))_(n)-G³, and—CH[C(O)N(R^(b))(R^(3b))][—(CR^(4b)R^(5b))_(n)-G³]; R^(b) is hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(3b) is hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; R^(4b) and R^(5b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; n, at eachoccurrence, is independently 1, 2, 3, 4, or 5; G¹ and G³ are eachindependently aryl or heteroaryl; wherein G¹ and G³ are eachindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl and—OR^(c); and R^(c) at each occurrence, is independently hydrogen orC₁-C₆-alkyl.

In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; m, at each occurrence, is independently 1, 2, or 3; R²is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and -G²;R³ is selected from the group consisting of—(CR^(4b)R^(5b))_(n)—C(O)N(R^(b))(G⁴), —(CR^(4b)R^(5b))_(n)—C(O)G⁴, -G²,and —(CR^(4b)R^(5b))_(n)-G⁴, -G²-G⁶; R^(b) is hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; R^(4b) and R^(5b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; n, at eachoccurrence, is independently 1, 2, 3, 4, or 5; G², G⁴ and G⁶ are eachindependently 3-6-membered-cycloalkyl or 4-10-membered-heterocycle;wherein G², G⁴ and G⁶ are each independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, benzyl, cyano,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo, —OR^(c), andphenyl, wherein phenyl and the phenyl ring of benzyl are optionallysubstituted with 1, 2, 3, or 4 C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy;and R^(c) at each occurrence, is independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl.

In one embodiment, R¹ is selected from the group consisting of5-(trifluoromethyl)pyridin-2-yl, 5-(difluoromethyl)pyridin-2-yl, and6-(trifluoromethyl)pyridin-3-yl; R² is selected from the groupconsisting of hydrogen and C₁-C₆-alkyl; R³ is -G²; and G² is a4-6-membered-cycloalkyl or 4-6-membered-heterocycle; wherein G² isunsubstituted or substituted with 1, 2, or 3 substituents selected fromthe group consisting of C₁-C₆-alkyl, halogen, and oxo.

In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; m, at each occurrence, is independently 1, 2, or 3;R², R³ and the nitrogen atom to which they are attached form a4-8-membered-monocylic heterocycle, 6-11-membered-bicyclic heterocycle,10-12-membered-tricyclic heterocycle, 7-11-membered-spirocyclicheterocycle or 8-11-membered-bicyclic heteroaryl comprised of a5-7-membered-monocyclic heterocycle fused to a 5-6-membered-monocyclicheteroaryl, wherein said 4-8-membered monocyclic heterocycle, said6-11-membered-bicyclic heterocycle, said 10-12-membered-tricyclicheterocycle, said 7-11-membered-spirocyclic heterocycle and said8-11-membered-bicyclic heteroaryl are unsubstituted or substituted with1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —OR^(1c),—O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —OC(O)R^(1c),—OC(O)N(R^(b))(R^(3c)), —SR^(1c), —S(O)R^(2c), —S(O)₂R^(2c), —S(O)₂G¹³,—S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)R^(1c),—(CR^(4c)R^(5c))_(p)—OC(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—SR^(1c), —(CR^(4c)R^(5c))_(p)—S(O)R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c), —(CR^(4c)R^(5c))_(p)—C(O)OR^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1c) andR^(3c), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4c) and R^(5c), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; p, at each occurrence, is independently 1, 2, 3, 4, or5; G¹¹ and G¹³ are each independently phenyl or 5-6-membered-heteroaryl;wherein G¹¹ and G¹³ are each independently unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹², and G¹⁴ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,benzyl, cyano, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo,—N(R^(e))C(O)R^(e), —N(R^(e))S(O)₂R^(f), —OR^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)N(R^(e))₂, —SO₂R^(f), —SO₂N(R^(e))₂, and phenyl,wherein phenyl and the phenyl ring of benzyl are optionally substitutedwith C₁-C₆-alkyl, halogen, or C₁-C₆-alkoxy; R^(e) at each occurrence, isindependently hydrogen, C₁-C₆-alkyl, aryl, or halo-C₁-C₆-alkyl; whereinsaid aryl is independently unsubstituted or substituted with 1, 2 3, 4,or 5 substituents independently selected from the group consisting ofC₁-C₆-alkyl, halo-C₁-C₆-alkyl, and halogen; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; m, at each occurrence, is independently 1, 2, or 3;R², R³ and the nitrogen atom to which they are attached form a4-8-membered-monocylic heterocycle, wherein said 4-8-membered monocyclicheterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, cyano, —OR^(1c),—O—(CR^(4c)R^(5c))_(p)—OR^(1c), —OG¹³, —SR^(1c), —S(O)R^(2c),—S(O)₂R^(2c), —S(O)₂G¹³, —S(O)₂G¹⁴, —S(O)₂N(R^(b))(R^(3c)),—S(O)₂—(CR^(4c)R^(5c))_(p)—C(O)OR^(1c), —S(O)₂—(CR^(4c)R^(5c))_(p)-G¹⁴,—C(O)R^(1c), —C(O)G¹⁴, —C(O)OR^(1c), —C(O)N(R^(b))(R^(3c)),—N(R^(b))(R^(3c)), —N(R^(a))C(O)R^(1c), —N(R^(a))C(O)G¹⁴,—N(R^(a))C(O)O(R^(1c)), —N(R^(a))C(O)N(R^(b))(R^(3c)),—N(R^(b))S(O)₂(R^(2c)), —N(R^(b))S(O)₂(G¹³),—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—O—(CR^(4c)R^(5c))_(p)—OR^(1c),—(CR^(4c)R^(5c))_(p)—S(O)R^(2c), —(CR^(4c)R^(5c))_(p)—S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—S(O)₂N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—C(O)N(R^(a))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)R^(1c),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(R^(1c)),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)O(CH₂G¹³),—(CR^(4c)R^(5c))_(p)—N(R^(a))C(O)N(R^(b))(R^(3c)),—(CR^(4c)R^(5c))_(p)—N(R^(b))S(O)₂(R^(2c)), -G¹¹,—(CR^(4c)R^(5c))_(p)-G¹³, —(CR^(4c)R^(5c))_(p)—OG¹³, -G¹²,—(CR^(4c)R^(5c))_(p)-G¹⁴, cyano-C₁-C₆-alkyl, oxo, C¹-C⁶-alkoxyimino andhalo-C₁-C₆-alkyl; R^(a) and R^(b), at each occurrence, are eachindependently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1c) andR^(3c), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2c), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4c) and R^(5c), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; p, at each occurrence, is independently 1, 2, 3, 4, or5; G¹¹ and G¹³ are each independently phenyl or 5-6-membered-heteroaryl;wherein G¹⁴ and G¹³ are each independently unsubstituted or substitutedwith 1, 2, 3, 4, or 5 substituents selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, cyano,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halogen, —N(R^(e))C(O)R^(e),and —OR^(e); G¹², and G¹⁴ are each independently3-6-membered-cycloalkyl, 3-6-membered-cycloalkenyl, or4-10-membered-heterocycle, wherein G¹² and G¹⁴ are each independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, cyano,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, halogen, oxo, —N(R^(e))C(O)R^(e),—N(R^(e))S(O)₂R^(f), —OR^(e), —C(O)R^(e), —C(O)N(R^(e))₂, —SO₂R^(f),—SO₂N(R^(e))₂; R^(e) at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; and R^(f) is C₁-C₆-alkyl orhalo-C₁-C₆-alkyl.

In one embodiment, R¹ is selected from the group consisting of5-(trifluoromethyl)pyridin-2-yl, 5-(difluoromethyl)pyridin-2-yl, and6-(trifluoromethyl)pyridin-3-yl; R², R³ and the nitrogen atom to whichthey are attached form an azetidine, pyrrolidine or piperazine, whereinsaid azetidine, pyrrolidine or piperazine is unsubstituted orsubstituted with 1, 2, or 3 substituents selected from the groupconsisting of C₁-C₆-alkyl, halogen, —OR^(1c),—(CR^(4e)R^(5c))_(p)—OR^(1c), -G¹², and halo-C₁-C₆-alkyl; R^(1c), ateach occurrence, is each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; R^(4c) and R^(5c), at each occurrence, are eachindependently hydrogen or C₁-C₆-alkyl; p, at each occurrence, isindependently 1, 2, or 3; and G¹², at each occurrence, is eachindependently 5-6-membered-heterocycle, wherein G¹² is eachindependently unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of C₁-C₆-alkyl, halogen, or oxo.

In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; m, at each occurrence, is independently 1, 2, or 3;R², R³ and the nitrogen atom to which they are attached form a6-11-membered-bicyclic heterocycle, 10-12-membered-tricyclicheterocycle, or 7-11-membered-spirocyclic heterocycle, wherein said6-11-membered-bicyclic heterocycle, said 10-12-membered-tricyclicheterocycle, or said 7-11-membered-spirocyclic heterocycle areunsubstituted or substituted with 1, 2, 3, or 4 substituents selectedfrom the group consisting of C₁-C₆-alkyl, halogen, —OR^(1c),—N(R^(b))(R^(3c)), —(CR^(4c)R^(5c))_(p)—OR^(1c), oxo, andhalo-C₁-C₆-alkyl; R^(b), at each occurrence, is independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(1c) and R^(3c), at each occurrence,are each independently hydrogen or C₁-C₆-alkyl; R^(4c) and R^(5c), ateach occurrence, are each independently hydrogen or C₁-C₆-alkyl; and p,at each occurrence, is independently 1, 2, 3, or 4.

In one embodiment, R¹ is 5- or 6-membered heteroaryl, wherein the 5- or6-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₆-alkyl, halogen,cyano, —OR^(1a), —S(O)₂R^(2a), —S(O)₂N(R^(b))(R^(3a)), —C(O)R^(1a),—(CR^(4a)R^(5a))_(m)—OR^(1a), and halo-C₁-C₆-alkyl; R^(b), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(1a) and R^(3a), at each occurrence, are each independently hydrogen,C₁-C₆-alkyl, or halo-C₁-C₆-alkyl; R^(2a), at each occurrence, isindependently C₁-C₆-alkyl or halo-C₁-C₆-alkyl; R^(4a) and R^(5a), ateach occurrence, are each independently hydrogen, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl; m, at each occurrence, is independently 1, 2, or 3;R², R³ and the nitrogen atom to which they are attached form a8-11-membered-bicyclic heteroaryl comprised of a 5-7-membered-monocyclicheterocycle fused to a 5-6-membered-monocyclic heteroaryl, wherein said8-11-membered-bicyclic heteroaryl are unsubstituted or substituted with1, 2, or 3 substituents selected from the group consisting ofC₁-C₆-alkyl, halogen, cyano, —OR^(1c), —S(O)₂R^(2c),—(CR^(4c)R^(5c))_(p)—OR^(1c), oxo, and halo-C₁-C₆-alkyl; R^(1c), at eachoccurrence, is independently hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;R^(2c), at each occurrence, is independently C₁-C₆-alkyl orhalo-C₁-C₆-alkyl; R^(4c) and R^(5c), at each occurrence, are eachindependently hydrogen and C₁-C₆-alkyl; and p, at each occurrence, isindependently 1, 2, 3, or 4.

Specific embodiments contemplated as part of the invention also include,but are not limited to, compounds of formula (I), as defined, forexample:

-   piperazin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [3-(morpholin-4-yl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1-(4-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}phenyl)ethanone;-   (3-aminoazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [cis-3,4-dihydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   pyrrolidin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(morpholin-4-yl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-methylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-methylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanone;-   N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-ethylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;

[(3R)-3-(hydroxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;

-   (3-hydroxyazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [3-(trifluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[2-(morpholin-4-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(2-methoxyethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(4,4-difluorocyclohexyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3S,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [2-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (8aS)-2-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one;-   [4-(2-hydroxy    ethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(methylsulfonyl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-(methoxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(dimethylamino)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(cis-3-hydroxycyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (3-fluoropyrrolidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   meso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(oxetan-2-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(2R)-2-hydroxypropyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   4,7-diazaspiro[2.5]oct-7-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2-oxopiperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(cis-3-methoxycyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(dimethylamino)-2-oxoethyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(3S)-3-methylpiperazin-1-yl]methanone;-   N-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(1-ethyl-5-oxopyrrolidin-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(1-ethyl-5-oxopyrrolidin-3-yl)quinoline-2-carboxamide;-   (4-cyclobutylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(3-methyloxetan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   meso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(8aS)-7,7-difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[1-(4-fluorophenyl)-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3R)-3-ethylpiperazin-1-yl]methanone;-   N-(2-methoxy    ethyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(difluoromethoxy)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanone;-   N-[(3R)-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3,3-difluorocyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [3-(methoxymethyl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-ethyl-N-(1-ethyl-2-oxopiperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-methylpiperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-(methoxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-(methoxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-[3-(methylsulfonyl)propyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (3-aminoazetidin-1-yl)(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(3,5-dimethylpiperazin-1-yl)methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(3R)-3-methylpiperazin-1-yl]methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3S)-3-(methoxymethyl)piperazin-1-yl]methanone;-   {3-[(3R)-3-fluoropyrrolidin-1-yl]azetidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3R)-3-(methoxymethyl)piperazin-1-yl]methanone;-   [(2S*)-2-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3R*)-1-methyl-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3S*)-1-methyl-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3,3,3-trifluoro-2-hydroxypropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   morpholin-4-yl[6-(pyridin-2-yloxy)quinolin-2-yl]methanone;-   (4-methylpiperazin-1-yl)    [6-(pyridin-2-yloxy)quinolin-2-yl]methanone;-   [3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl][6-(pyridin-2-yloxy)quinolin-2-yl]methanone;-   N-[2-(piperidin-1-yl)ethyl]-6-(pyridin-2-yloxy)quinoline-2-carboxamide;-   6-(pyridin-2-yloxy)-N-(1,2,4-thiadiazol-5-yl)quinoline-2-carboxamide;-   4-({2-[(4-methylpiperazin-1-yl)carbonyl]quinolin-6-yl}oxy)benzonitrile;-   6-(4-cyanophenoxy)-N-[2-(piperidin-1-yl)ethyl]quinoline-2-carboxamide;-   4-{[2-(morpholin-4-ylcarbonyl)quinolin-6-yl]oxy}benzonitrile;-   6-(4-cyanophenoxy)-N-(1H-indazol-6-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[3-(dimethylamino)propyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[2-(morpholin-4-yl)ethyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[3-(morpholin-4-yl)propyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1,3-thiazol-2-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(pyridin-3-ylmethyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(3S)-2-oxotetrahydrofuran-3-yl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(2R)-1-hydroxy-3-methylbutan-2-yl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-thienylmethyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[2-(2-thienyl)ethyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-furylmethyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1-hydroxy-3-methylbutan-2-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[2-(pyrrolidin-1-yl)ethyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(pyridin-2-ylmethyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(pyridin-4-ylmethyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(5-methyl-2-furyl)methyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[3-(piperidin-1-yl)propyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(4-phenoxyphenyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[3-(trifluoromethoxy)benzyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(4-methylbenzyl)quinoline-2-carboxamide;-   N-(1,3-benzodioxol-5-ylmethyl)-6-(4-cyanophenoxy)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2,3-dimethoxybenzyl)quinoline-2-carboxamide;-   4-{[2-(azepan-1-ylcarbonyl)quinolin-6-yl]oxy}benzonitrile;-   6-(4-cyanophenoxy)-N-(2-methoxy    ethyl)-N-propylquinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-ethoxyethyl)quinoline-2-carboxamide;-   N-(1-benzylpyrrolidin-3-yl)-6-(4-cyanophenoxy)quinoline-2-carboxamide;-   4-[(2-{[3-(trifluoromethyl)piperidin-1-yl]carbonyl}quinolin-6-yl)oxy]benzonitrile;-   4-{[2-(2,3-dihydro-1H-indol-1-ylcarbonyl)quinolin-6-yl]oxy}benzonitrile;-   4-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}benzonitrile;-   6-(4-cyanophenoxy)-N-[(3R)-2-oxotetrahydrofuran-3-yl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(tetrahydrofuran-3-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(methylsulfonyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(tetrahydro-2H-pyran-3-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(3R)-tetrahydrofuran-3-yl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(3S)-tetrahydrofuran-3-yl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1R,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1S,2S)-2-hydroxycyclopentyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-hydroxy-2-methylpropyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[1-(hydroxymethyl)cyclopropyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(trans-4-hydroxycyclohexyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1,3-dihydroxy    propan-2-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1-hydroxy propan-2-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-hydroxypropyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1S,3R)-3-hydroxycyclohexyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1S,3R)-3-hydroxycyclopentyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1R,2S)-2-hydroxycyclopentyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(1S,3S)-3-hydroxycyclohexyl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(cis-4-hydroxycyclohexyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(3-hydroxybutan-2-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-hydroxy-3-methylbutyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1,1-dioxidotetrahydrothiophen-3-yl)quinoline-2-carboxamide;-   4-({2-[(3-oxopiperazin-1-yl)carbonyl]quinolin-6-yl}oxy)benzonitrile;-   4-[(2-{[4-(morpholin-4-yl)piperidin-1-yl]carbonyl}quinolin-6-yl)oxy]benzonitrile;-   6-(4-cyanophenoxy)-N-[(4R)-6-fluoro-3,4-dihydro-2H-chromen-4-yl]quinoline-2-carboxamide;-   4-({2-[(4-tert-butylpiperazin-1-yl)carbonyl]quinolin-6-yl}oxy)benzonitrile;-   6-(4-cyanophenoxy)-N-[(4R)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]quinoline-2-carboxamide;-   4-[(2-{[(3S)-3-isopropylpiperazin-1-yl]carbonyl}quinolin-6-yl)oxy]benzonitrile;-   6-(4-cyanophenoxy)-N-(1-methyl-2-oxopyrrolidin-3-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(1,3-oxazol-2-ylmethyl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[2-(methylamino)-2-oxoethyl]quinoline-2-carboxamide;-   N-(2-amino-2-oxoethyl)-6-(4-cyanophenoxy)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-(2-sulfamoylethyl)quinoline-2-carboxamide;-   4-({2-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]quinolin-6-yl}oxy)benzonitrile;-   N-(tetrahydrofuran-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(2-amino-2-oxoethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(pyridin-2-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   piperazin-1-yl(6-{[4-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl(6-{[6-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-N-(1,1-dioxidotetrahydrothiophen-3-yl)quinoline-2-carboxamide;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-6-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}quinoline-2-carboxamide;-   2-oxa-6-azaspiro[3.3]hept-6-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   2,6-diazaspiro[3.3]hept-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-[(5-cyanopyridin-2-yl)oxy]-N-(1,1-dioxidotetrahydrothiophen-3-yl)quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]quinoline-2-carboxamide;-   6-(4-cyanophenoxy)-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]quinoline-2-carboxamide;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-6-[(5-methylpyrimidin-2-yl)oxy]quinoline-2-carboxamide;-   6-[(4,6-dimethylpyrimidin-2-yl)oxy]-N-(1,1-dioxidotetrahydrothiophen-3-yl)quinoline-2-carboxamide;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-6-[(4-methylpyrimidin-2-yl)oxy]quinoline-2-carboxamide;-   (3 aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2    (1H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-[(6-chloropyridazin-3-yl)oxy]-N-(1,1-dioxidotetrahydrothiophen-3-yl)quinoline-2-carboxamide;-   (3    aR,6aR)-5-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one;-   (3aR,4R,7S,7aS)-octahydro-1H-4,7-epiminoisoindol-8-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-6-{[6-(trifluoromethyl)pyridazin-3-yl]oxy}quinoline-2-carboxamide;-   8-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one;-   5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   8-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione;-   4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-2-one;-   5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[2-(pyrrolidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(piperidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [4-(methylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(isopropylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(phenylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2R,4R)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(2,2,2-trifluoroethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(pyridin-2-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(pyridin-3-ylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(piperidin-1-ylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(morpholin-4-ylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   methyl    4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate;-   N,N-dimethyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxamide;-   5-methyl-8-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-oxa-5,8-diazaspiro[3.5]nonan-6-one;-   2-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;-   (3,3-difluoro-4-hydroxypiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [cis-3-fluoro-4-hydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [cis-4-fluoro-3-hydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4,4-difluoro-3-hydroxypiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [trans-3-ethyl-2-(hydroxymethyl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [trans-3-fluoro-4-hydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [trans-4-fluoro-3-hydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(2R)-2,3,3-trimethylazetidin-1-yl]methanone;-   (3-hydroxy-3-methylazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(methoxymethyl)-3-methylazetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3-methyl-3-phenoxyazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3-phenoxyazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(1H-imidazol-1-yl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(4-chlorophenoxy)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(2S)-2,3,3-trimethylazetidin-1-yl]methanone;-   [3-(4-bromophenoxy)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(hydroxymethyl)-3-methylazetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   3-phenyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-2-one;-   {6-[4-(2-hydroxypropan-2-yl)phenoxy]quinolin-2-yl}(piperazin-1-yl)methanone;-   6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (4-methylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (8S,9aS)-8-hydroxy-2-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one;-   (1S,6R)-3,8-diazabicyclo[4.2.0]oct-3-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {6-[4-(methylsulfonyl)phenoxy]quinolin-2-yl}(piperazin-1-yl)methanone;-   piperazin-1-yl(6-{4-[(trifluoromethyl)sulfonyl]phenoxy}quinolin-2-yl)methanone;-   N-(azetidin-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [3-(pyridin-3-yl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1-{4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}ethanone;-   1,4-diazepan-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   2,5-dihydro-1H-pyrrol-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   thiomorpholin-4-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   3,4-dihydro-2,7-naphthyridin-2(1H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2R,4S)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-{(2R,3S)-2-phenyl-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]pyrrolidin-3-yl}-4-(trifluoromethyl)benzenesulfonamide;-   1-(6-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}pyridin-3-yl)ethanone;-   (1,1-dioxidothiomorpholin-4-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-tert-butylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {6-[(5-fluoropyridin-2-yl)oxy]quinolin-2-yl}(piperazin-1-yl)methanone;-   N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (4-isopropylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   2,7-diazaspiro[3.5]non-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   tetrahydropyrimidin-1    (2H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2S)-2-(hydroxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-methyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-sulfonamide;-   N-ethyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-sulfonamide;-   [(2S)-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   azepan-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-methyl-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-L-prolinamide;-   1,4-dioxa-8-azaspiro[4.5]dec-8-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl[6-(pyrimidin-2-yloxy)quinolin-2-yl]methanone;-   [(2R)-2-(hydroxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {6-[(5-fluoropyrimidin-2-yl)oxy]quinolin-2-yl}(piperazin-1-yl)methanone;-   piperazin-1-yl(6-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl(6-{[6-(trifluoromethyl)pyridazin-3-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl(6-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3    aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl    {6-[4-(trifluoromethyl)phenoxy]quinolin-2-yl}methanone;-   (6-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanone;-   N-[2-(methylsulfonyl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [4-(oxetan-3-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   3,4-dihydroisoquinolin-2(1H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(methylsulfonyl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-hydroxy-4-methylpiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-hydroxypiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(1R,4R,6R)-6-(hydroxymethyl)-2-azabicyclo[2.2.1]hept-2-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(1R,4R,6S)-6-(hydroxymethyl)-2-azabicyclo[2.2.1]hept-2-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3    aR,4R,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (4-methyl-1,4-diazepan-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-cyclopropylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-phenylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-isopropylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(piperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [4-(hydroxymethyl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(8-azabicyclo[3.2.1]oct-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [4-(pyrazin-2-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(pyridin-3-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(pyrimidin-2-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(pyridazin-3-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(5-chloropyridin-2-yl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-ethylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-isopropylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {6-[4-(1-hydroxyethyl)phenoxy]quinolin-2-yl)}(piperazin-1-yl)methanone;-   [(3S)-3-(hydroxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   isopropyl    4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate;-   (1S,5S)-3,6-diazabicyclo[3.2.0]hept-3-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1,6-diazaspiro[3.3]hept-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3 aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5    (1H)-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(morpholin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-hydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-hydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-hydroxy    azepan-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   {4-[(3-methyloxetan-3-yl)methyl]piperazin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(methylsulfonyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   2-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;-   ethyl    4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate;-   cyclopropyl{4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}methanone;-   (4-cyclohexylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3-fluoro-4-hydroxypyrrolidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   isobutyl    4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate;-   (4-ethylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[3-bromo-5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanone;-   morpholin-4-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperidin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(2,2-difluoroethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   morpholin-4-yl    {4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}methanone;-   [(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethoxy)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(trans-3-hydroxycyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [trans-3,4-dihydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2R,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [trans-3-hydroxy-4-methoxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [trans-3-hydroxy-4-methylpyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [cis-3,5-bis(hydroxymethyl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(pyridin-2-ylmethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   3,3-dimethyl-1-{4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}butan-1-one;-   [(3R)-3-aminopyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[4-(3,3,3-trifluoropropyl)piperazin-1-yl]methanone;-   (3,3-difluoropiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(5S,7S)-7-hydroxy-1-azaspiro[4.4]non-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(azetidin-1-yl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(1,3-oxazol-4-ylmethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(morpholin-4-yl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2-sulfamoylethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (4-fluoropiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-(piperidin-1-yl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl(6-{[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy}quinolin-2-yl)methanone;-   N-isopropyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-2-carboxamide;-   N-methyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-2-carboxamide;-   rac-[(3R,4S)-3,4-dihydroxy-2,5-dimethylpyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [cis-3,4-dimethoxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3S)-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperidine-3-carboxamide;-   N-(2-hydroxyethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(tetrahydro-2H-pyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}nicotinonitrile;-   7-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydro[1,3]oxazolo[3,4-a]pyrazin-3-one;-   (4,4-difluoropiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3R)-pyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    {4-[(3,3,3-trifluoropropyl)sulfonyl]piperazin-1-yl}methanone;-   (8aR)-7-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydro[1,3]oxazolo[3,4-a]pyrazin-3-one;-   N-(3-hydroxy-3-methylbutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(2R)-pyrrolidin-2-ylmethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(1-hydroxycyclobutyl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(2-oxopyrrolidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(2-aminoethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [2-(hydroxymethyl)morpholin-4-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [2-(fluoromethyl)morpholin-4-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (1-hydroxy-7-azaspiro[3.5]non-7-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one;-   4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-1,4-diazepan-2-one;-   N-(2,2,2-trifluoroethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (2-hydroxy-6-azaspiro[3.4]oct-6-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2-fluoroethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(2,2-difluoroethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3S,4S)-3-hydroxy-4-(methylsulfanyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [cis-3,4-dihydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [trans-3-hydroxy-4-(methylsulfonyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1,4-dioxa-7-azaspiro[4.4]non-7-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [4-(methoxyimino)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (2-hydroxy-7-azaspiro[3.5]non-7-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-N-(3,3,3-trifluoropropyl)quinoline-2-carboxamide;-   [(7S,8aR)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R,7S,8aR)-7-fluoro-3-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R,8aR)-7,7-difluoro-3-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(7S,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(4-benzylmorpholin-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(2S)-pyrrolidin-2-ylmethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3,3-dimethylazetidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(thiomorpholin-4-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-allyl-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidine-3-carbonitrile;-   [cis-3-hydroxy-4-(methoxymethoxy)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(1-hydroxycyclopropyl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-one;-   N-(4-hydroxytetrahydrofuran-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   5-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}pyrazine-2-carbonitrile;-   [cis-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {2-[(dimethylamino)methyl]morpholin-4-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperidin-4-one;-   N,N-di(tetrahydro-2H-pyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   {4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]piperidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]piperidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N,N-bis(2-methoxyethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[1-(hydroxymethyl)cyclopropyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [4-(tetrahydrofuran-3-ylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   methyl    ({4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}sulfonyl)acetate;-   [4-(tetrahydro-2H-pyran-4-ylsulfonyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]sulfonyl}piperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {4-[(tetrahydrofuran-3-ylmethyl)sulfonyl]piperazin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {4-[(1,1-dioxidotetrahydrothiophen-3-yl)sulfonyl]piperazin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {4-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperazin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[4-methyl-5-({4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}sulfonyl)-1,3-thiazol-2-yl]acetamide;-   N-[5-({4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}sulfonyl)-1,3-thiazol-2-yl]acetamide;-   {4-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperazin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3S)-tetrahydrofuran-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(2-methoxyethyl)-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3R)-tetrahydrofuran-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(2S)-tetrahydrofuran-2-ylmethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R,5R)-3,5-dihydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3-methoxyazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(trans-3-methoxycyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl)-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(oxetan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(tetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(1S,2R)-2-hydroxycyclopentyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-2-carboxamide;-   (4-aminopiperidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3,3-difluoropyrrolidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3,3-dimethylpyrrolidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-fluoro-1,4-diazepan-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-hydroxy-1,4-diazepan-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-{1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperidin-4-yl}methanesulfonamide;-   N-[(2R)-tetrahydrofuran-2-ylmethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(2S)-2-hydroxypropyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-methyl-N-(tetrahydro-2H-pyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3-hydroxyoxetan-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[3-(trifluoromethyl)pyrrolidin-1-yl]methanone;-   (3,4-difluoropyrrolidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(6-oxopiperidin-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (6,6-difluoro-1,4-diazepan-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   5,8-diazaspiro[3.5]non-8-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(1,1-dioxidotetrahydrothiophen-3-yl)-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(tetrahydrothiophen-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(2-oxoimidazolidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(pyridin-2-ylamino)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(1H-imidazol-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(azetidin-2-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3R,4R)-4-hydroxy-1,1l-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3-hydroxy-3-methylcyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [3-(2-methoxyethoxy)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-{1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-yl}methanesulfonamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [3-(morpholin-4-yl)azetidin-1-yl]methanone;-   [2-(difluoromethyl)piperazin-1-yl](6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   piperazin-1-yl(6-{[5-(trifluoromethoxy)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(3-oxocyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-(morpholin-4-yl)cyclobutyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(2-hydroxy-2-methylpropyl)quinoline-2-carboxamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [4-(morpholin-4-yl)piperidin-1-yl]methanone;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(2,2,2-trifluoroethyl)quinoline-2-carboxamide;-   N-(4,4-difluorocyclohexyl)-6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{(3R)-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]pyrrolidin-3-yl}acetamide;-   N-{(3R)-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]pyrrolidin-3-yl}cyclopropanecarboxamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(3R)-3-(hydroxymethyl)piperazin-1-yl]methanone;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[2-(dimethylamino)-2-oxoethyl]quinoline-2-carboxamide;-   N-{2-[(2-methoxyethyl)amino]-2-oxoethyl}-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(morpholin-4-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-(morpholin-4-yl)-3-oxopropyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-oxo-3-(pyrrolidin-1-yl)propyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(diethylamino)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-oxo-2-(piperidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(1-methyl-5-oxopyrrolidin-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-oxo-3-(piperidin-1-yl)propyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   1-methyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-2-one;-   N,N-dimethyl-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    carbonyl]-L-prolinamide;-   N-[2-(cyclopropylamino)-2-oxoethyl]-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-(diethylamino)-3-oxopropyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(isopropylamino)-2-oxoethyl]-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   1-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-N-methyl-L-prolinamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[2-oxo-2-(pyrrolidin-1-yl)ethyl]quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-{2-[(2-methoxyethyl)amino]-2-oxoethyl}-N-methylquinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[2-(morpholin-4-yl)-2-oxoethyl]quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[3-(morpholin-4-yl)-3-oxopropyl]quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[3-oxo-3-(pyrrolidin-1-yl)propyl]quinoline-2-carboxamide;-   N-[2-(diethylamino)-2-oxoethyl]-6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(1-methyl-5-oxopyrrolidin-3-yl)quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[3-oxo-3-(piperidin-1-yl)propyl]quinoline-2-carboxamide;-   4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-1-methylpiperazin-2-one;-   1-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-N,N-dimethyl-L-prolinamide;-   N-[2-(cyclopropylamino)-2-oxoethyl]-6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-methylquinoline-2-carboxamide;-   N-[3-(diethylamino)-3-oxopropyl]-6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[2-(isopropylamino)-2-oxoethyl]-N-methylquinoline-2-carboxamide;-   N-[2-(2-oxopiperazin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(azetidin-3-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(2-hydroxy-2-methylpropyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   4-{4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}butanenitrile;-   3-{4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-yl}propanenitrile;-   1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperidine-4-carbonitrile;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(oxetan-3-yl)quinoline-2-carboxamide;-   5,8-dioxa-2-azaspiro[3.4]oct-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-[(3S,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]quinoline-2-carboxamide;-   tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [3-(methylsulfonyl)azetidin-1-yl]methanone;-   N-methyl-N-(oxetan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)quinoline-2-carboxamide;-   N-(oxetan-3-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-2-carbonitrile;-   6-(4-cyanophenoxy)-N-(2-oxopiperidin-4-yl)quinoline-2-carboxamide;-   N-(3,3-difluorocyclopentyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3,3-difluorocyclopentyl)-6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [3-fluoro-3-(methoxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(ethoxymethyl)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {3-fluoro-3-[(pyridin-4-yloxy)methyl]pyrrolidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   {3-fluoro-3-[(pyridin-3-yloxy)methyl]pyrrolidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-fluoro-3-(phenoxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   benzyl    ({4-fluoro-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]pyrrolidin-3-yl}methyl)carbamate;-   {3-fluoro-3-[(2-methoxyethoxy)methyl]pyrrolidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   2-oxa-6-azaspiro[3.4]oct-6-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1-(3-methoxyphenyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-2-one;-   N-(thietan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{3-[(2-methylphenyl)amino]-3-oxopropyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(2S)-1-(dimethylamino)-1-oxo-3-phenylpropan-2-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[1-(2-methoxyphenyl)-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(1-oxidothietan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(1,1-dioxidothietan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-oxa-1-azaspiro[3.3]hept-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1-{1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-yl}ethanone;-   (3-fluoroazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (3,3-difluoroazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   (4R)-4-fluoro-N,N-dimethyl-1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-L-prolinamide;-   [4-(1,3-oxazol-2-ylmethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(4,4-difluorocyclohexyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[(4S)-2-oxopiperidin-4-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-{2-[(2-methoxyethyl)amino]-2-oxoethyl}-N-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[3-(morpholin-4-yl)-3-oxopropyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[3-oxo-3-(pyrrolidin-1-yl)propyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[2-(diethylamino)-2-oxoethyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[2-oxo-2-(piperidin-1-yl)ethyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-(1-methyl-5-oxopyrrolidin-3-yl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[3-oxo-3-(piperidin-1-yl)propyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[(4R)-2-oxopiperidin-4-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(cyclopropylamino)-2-oxoethyl]-N-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-(1-ethyl-5-oxopyrrolidin-3-yl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[3-(diethylamino)-3-oxopropyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[2-(isopropylamino)-2-oxoethyl]-N-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   [4-(morpholin-4-yl)piperidin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   meso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-methyl-N-(1-methyl-2-oxopiperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(3R)-2-oxotetrahydrofuran-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   {4-[(2-methyl-1,3-oxazol-4-yl)methyl]piperazin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-oxa-2-azaspiro[3.4]oct-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   6-oxa-2-azaspiro[3.5]non-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(methylsulfonyl)azetidin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-(oxetan-3-yl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[(3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[(3S,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   2,5-dihydro-1H-pyrrol-1-yl(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2-methoxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(8aS)-7,7-difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-ethylpiperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [(3R)-3-(hydroxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-(hydroxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [cis-3,4-dihydroxypyrrolidin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-[2-(trifluoromethoxy)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-fluoropyrrolidin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-methylpiperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-fluoropyrrolidin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-(3,3,3-trifluoro-2-hydroxypropyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   (3,5-dimethylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-ethylpiperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   [3-(morpholin-4-yl)azetidin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone;-   N-(3,3-difluorocyclobutyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-(3-oxocyclobutyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   [3-(piperazin-1-yl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   4,7-diazaspiro[2.5]oct-7-yl(6-{[5-(difluoromethyl)pyri    din-2-yl]oxy}quinolin-2-yl)methanone;-   N-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{2-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{2-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{2-[(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(1,1-dioxido-1,3-thiazolidin-3-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3-methoxyazetidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-l1-yl]-2-oxoethyl}-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(azetidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-oxo-2-(3-oxopyrrolidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-(morpholin-4-yl)cyclobutyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(3R)-3-fluoropyrrolidin-1-yl]methanone;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(3S)-3-fluoropyrrolidin-1-yl]methanone;-   N-(methylsulfonyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3-hydroxy-3-methylcyclobutyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide;-   N-[1-(dimethylamino)-1-oxopropan-2-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3,3-difluorocyclobutyl)-6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-hydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-hydroxypiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3R,4R)-4-amino-3-fluoropiperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-[(3R,4R)-3-fluoropiperidin-4-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   (6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)    [(3S)-3-(hydroxymethyl)piperazin-1-yl]methanone;-   {3-[(3S)-3-fluoropyrrolidin-1-yl]azetidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(1-methyl-2-oxopyrrolidin-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(3R)-3-methoxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [(3S)-3-methoxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2-methoxypropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(1-methoxycyclobutyl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(3-oxocyclobutyl)quinoline-2-carboxamide;-   [(3S)-3-(methoxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(3-cyanopropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-cyclobutyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   azetidin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [2-(trifluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(3-methoxypropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(thietan-3-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(1-oxidothietan-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(1,1-dioxidothietan-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   [(2R)-2-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(3-fluorocyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[2-(pyridin-2-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-(pyridin-2-yl)propyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[3-(2-oxopyrrolidin-1-yl)propyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[(5-oxopyrrolidin-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3-acetamido-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-methyl-N-[2-(methylsulfonyl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-[4-(methylsulfonyl)butyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-(3-acetamidopropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydropyrrolo[1,2-a]pyrimidin-6(2H)-one;-   N-[2-(1,1-dioxidothietan-3-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   N-methyl-N-(2,2,2-trifluoroethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;-   6-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(3-fluorocyclobutyl)quinoline-2-carboxamide;-   [4-fluoro-4-(methoxymethyl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   [3-(2,2-difluoroethoxy)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   1,1-dimethyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazin-1-iumiodide;-   {3-[(2,2,2-trifluoroethyl)amino]azetidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone;-   N-(2,2-difluoroethyl)-N-methyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide;    and-   7-oxa-2-azaspiro[3.5]non-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone.

Compound names are assigned by using Name 2012 naming algorithm byAdvanced Chemical Development or Struct=Name naming algorithm as part ofCHEMDRAW® ULTRA v. 12.0.2.1076.

Compounds of the invention may exist as stereoisomers wherein asymmetricor chiral centers are present. These stereoisomers are “R” or “S”depending on the configuration of substituents around the chiral carbonatom. The terms “R” and “S” used herein are configurations as defined inIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of compounds of the invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by methods of resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

On occasion, the relative stereochemistry of an enantiomeric pair isknown, however, the absolute configuration is not known. In thatcircumstance, the relative stereochemistry descriptor terms “R*” and“S*” are used. The terms “R*” and “S*” used herein are defined in Eliel,E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley &Sons, Inc.: New York, 1994; pp 119-120 and 1206.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutane may be present in the cis or trans configuration, and may bepresent as a single isomer or a mixture of the cis and trans isomers.Individual cis or trans isomers of compounds of the invention may beprepared synthetically from commercially available starting materialsusing selective organic transformations, or prepared in single isomericform by purification of mixtures of the cis and trans isomers. Suchmethods are well-known to those of ordinary skill in the art, and mayinclude separation of isomers by recrystallization or chromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes suitable for inclusion in the compoundsof the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Compounds incorporating positron-emitting isotopes are useful in medicalimaging and positron-emitting tomography (PET) studies for determiningthe distribution of receptors. Suitable positron-emitting isotopes thatcan be incorporated in compounds of formula (I) are ¹¹C, ¹³N, ¹⁵O, and¹⁸F. Isotopically-labeled compounds of formula (I) can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesusing appropriate isotopically-labeled reagent in place ofnon-isotopically-labeled reagent.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods which illustrate ameans by which the compounds can be prepared.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-2.

As shown in Scheme 1, compounds of formula (1-6) can be prepared in a5-step sequence starting with quinoline-2,6-diol, (1-1). Treatment ofquinoline-2,6-diol, (1-1), with phosphoryl chloride in heatedN,N-dimethylformamide gives 2-chloroquinolin-6-ol, (1-2).2-Chloroquinolin-6-ol, (1-2), can then be carbonylated with carbonmonoxide (40-70 psi) in the presence of a palladium catalyst such as butnot limited to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂) and a tertiary amine base such as triethyl amine in heated(90-110° C.) methanol to supply methyl 6-hydroxyquinoline-2-carboxylate,(1-3). Methyl 6-hydroxyquinoline-2-carboxylate, (1-3), can then bereacted with X¹—R¹, wherein X¹ is a halogen or sulfonate and R¹ is asdescribed in the Summary, in the presence of a base such as cesiumcarbonate or potassium carbonate in a heated (60-140° C.) aproticsolvent such as N,N-dimethylformamide or N-methyl-2-pyrrolidinone togive compounds of formula (1-4). The ester of compounds of formula (1-4)can be hydrolyzed with a base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide in a mixture of water andtetrahydrofuran to give compounds of formula (1-5). Compounds of formula(1-5) can be reacted with amines or heterocycles, HNR²R³, wherein R² andR³ are as described in the Summary, under amide bond forming conditionsto give compounds of formula (1-6). Examples of conditions known togenerate amides from a mixture of a carboxylic acid and an amine includebut are not limited to adding a coupling reagent such as but not limitedto N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI),1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinicchloride (BOPCl),2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate or1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V) (HBTU), and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®).The coupling reagents may be added as a solid, a solution, or as thereagent bound to a solid support resin. In addition to the couplingreagents, auxiliary-coupling reagents may facilitate the couplingreaction. Auxiliary coupling reagents that are often used in thecoupling reactions include but are not limited to(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as triethylamine ordiisopropylethylamine. The coupling reaction may be carried out insolvents such as but not limited to tetrahydrofuran,N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide,dichloromethane, and ethyl acetate. The compounds of formula (1-6) arerepresentative of compounds of formula (I). Compounds of formula (1-6)can be further transformed using the methodologies described in theExamples to give additional compounds of formula (I).

As shown in Scheme 2, compounds of formula (1-6) can also be prepared inan alternative sequence starting with methyl6-hydroxyquinoline-2-carboxylate, (1-3). Methyl6-hydroxyquinoline-2-carboxylate, (1-3), can be hydrolyzed at or nearambient temperature with a base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide in a mixture of water andtetrahydrofuran to give 6-hydroxyquinoline-2-carboxylic acid, (2-1).6-Hydroxyquinoline-2-carboxylic acid, (2-1), can be reacted with aminesor heterocycles, HNR²R³, wherein R² and R³ are as described in theSummary, under amide bond forming conditions to give compounds offormula (2-2). Examples of conditions known to generate amides from amixture of a carboxylic acid and an amine are described in Scheme 1 forthe conversion of compounds of formula (1-5) to compounds of formula(1-6). Compounds of formula (2-2), can then be reacted with X¹—R¹,wherein X¹ is a halogen or sulfonate and R¹ is as described in theSummary, in the presence of a base such as cesium carbonate or potassiumcarbonate in a heated (60-140° C.) aprotic solvent such asN,N-dimethylformamide or N-methyl-2-pyrrolidinone to give compounds offormula (1-6). The compounds of formula (1-6) are representative ofcompounds of formula (I). Compounds of formula (1-6) can be furthertransformed using the methodologies described in the Examples to giveadditional compounds of formula (I).

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, reversed phase C8- or C18-bonded silica,alumina, or silica derivatized with alkylsilane groups using elutionwith water, organic solvents, or solvent combinations with or withoutthe addition buffers or other additives such as trifluoroacetic acid orammonium acetate, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England. Basic amine containing compounds purified usingchromatography in the presence of additives such as trifluoroaceticacid, may be isolated as salts.

Many of the compounds of the invention have at least one basic nitrogenwhereby the compound can be treated with an acid to form a desired salt.For example, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic,carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic,hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric,camphorsulfonic, malic, phenylacetic, aspartic, trifluoroacetic acid orglutamic acid, and the like.

Optimum reaction conditions and reaction times for each individual stepcan vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions can be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions can be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or can beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that cannot be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in PGM Wuts and TW Greene, in Greene's book titled ProtectiveGroups in Organic Synthesis (4^(th) ed.), John Wiley & Sons, NY (2006),which is incorporated herein by reference in its entirety. Synthesis ofthe compounds of the invention can be accomplished by methods analogousto those described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it can be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it can be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

It can be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection, for topical administration, orfor rectal administration.

The term “pharmaceutically acceptable carrier”, as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally”, as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials which can be useful for delaying releaseof the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention. The ointments, pastes, creams and gels maycontain, in addition to an active compound of this invention, animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which canbe required. Ophthalmic formulations, eye ointments, powders andsolutions are contemplated as being within the scope of this invention.Aqueous liquid compositions comprising compounds of the invention alsoare contemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts or esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable saltsand esters and amides”, as used herein, refer to carboxylate salts,amino acid addition salts, zwitterions, and esters and amides ofcompounds of formula (I) which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response, andthe like, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid. An example of a suitable salt is a hydrochloride salt.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Preferred salts of thecompounds of the invention are the tartrate and hydrochloride salts.Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.

Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,ethylammonium and the like. Other representative organic amines usefulfor the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

The term “pharmaceutically acceptable ester”, as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆-alkyl esters andC₅-to-C₇-cycloalkyl esters, although C₁-to-C₄-alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound that containsthe hydroxy group with acid and an alkylcarboxylic acid such as aceticacid, or with acid and an arylcarboxylic acid such as benzoic acid. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl triflate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsomay be prepared by reaction of the compound with an acid such ashydrochloric acid and an alcohol such as methanol or ethanol.

The term “pharmaceutically acceptable amide”, as used herein, refers tonon-toxic amides of the invention derived from ammonia, primaryC₁-to-C₆-alkyl amines and secondary C₁-to-C₆-dialkyl amines. In the caseof secondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃-alkyl primary amides and C₁-to-C₂-dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) may beprepared according to conventional methods. Pharmaceutically acceptableamides are prepared from compounds containing primary or secondary aminegroups by reaction of the compound that contains the amino group with analkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In thecase of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also may beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

The compounds and compositions of the invention are useful for treatingand preventing certain diseases and disorders in humans and animals. Asan important consequence of the ability of the compounds of theinvention to modulate the effects of voltage-gated sodium channels(e.g., Na_(v)1.7 and Na_(v)1.8) in cells, the compounds described in theinvention can affect physiological processes in humans and animals. Inthis way, the compounds and compositions described in the invention areuseful for treating and preventing diseases and disorders modulated byvoltage-gated sodium channels, e.g., Na_(v)1.7 and Na_(v)1.8. Typically,treatment or prevention of such diseases and disorders can be effectedby selectively modulating voltage-gated sodium channels, e.g., Na_(v)1.7and Na_(v)1.8, in a mammal, by administering a compound or compositionof the invention, either alone or in combination with another activeagent as part of a therapeutic regimen.

The terms “treat,” “treating,” and “treatment” are readily understood bya physician of ordinary skill and, with respect to treatment of aparticular condition, can include ameliorating, suppressing,eradicating, preventing, reducing the risk of, and/or delaying the onsetof the disease being treated.

The term “subject” includes animals such as mammals, including primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice and the like. The methods of treatment are particularly suitablefor use with a human subject, but may be used with other animalsubjects, particularly mammals.

One embodiment of the present invention provides a method of treatingpain in a subject in need thereof. The method comprises administering tothe subject, including a mammal, such as a human, a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof. Conditions related to pain include, forexample, acute pain, chronic pain, neuropathic pain, nociceptive pain,allodynia, inflammatory pain, inflammatory hyperalgesia, post herpeticneuralgia, post-operative pain, post-stroke pain, neuropathies,neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury,rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, eyepain, visceral pain, cancer pain, dental pain, headache, migraine,carpal tunnel syndrome, knee pain, fibromyalgia, neuritis, sciatica,pelvic hypersensitivity, pelvic pain, menstrual pain.

Pain generally can be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain include neuropathic pain (e.g., painful diabeticneuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain,headache, cancer pain, arthritic pain and chronic post-surgical pain. Inone embodiment, the condition related to pain is chronic pain. Inanother embodiment, the condition related to pain is acute pain.

Pain also can be divided into a number of different subtypes accordingto differing pathophysiology, including neuropathic, nociceptive, andinflammatory pain. Some types of pain have multiple etiologies and canbe classified in more than one area, e.g., back pain and cancer painhave both nociceptive and neuropathic components.

In one embodiment, the condition related to pain is selected from thegroup consisting of neuropathic pain, nociceptive pain, and inflammatorypain.

In another embodiment, the condition related to pain is neuropathicpain. Neuropathic pain generally is defined as pain initiated or causedby a primary lesion or dysfunction in the nervous system and can result,for example, from trauma or disease. The term neuropathic painencompasses many conditions with diverse etiologies including peripheralneuropathy, diabetic neuropathy, post-herpetic neuralgia, trigeminalneuralgia, back pain, cancer neuropathy, HIV-neuropathy, phantom limbpain, carpal tunnel syndrome, central post-stroke pain, and painassociated with chronic alcoholism, hypothyroidism, uremia, multiplesclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamindeficiency.

In another embodiment, the condition related to pain is nociceptivepain. Nociceptive pain is induced by tissue injury or by intense stimuliwith the potential to cause injury. When a substantial injury occurs tobody tissue through trauma or disease, the characteristics of nociceptoractivation are altered and there is sensitization in the peripheryleading to a heightened sensation of pain in the subject. Moderate tosevere acute nociceptive pain is a prominent feature of pain fromcentral nervous system trauma, strains/sprains, burns, myocardialinfarction and acute pancreatitis, post-operative pain (pain followingany type of surgical procedure), post-traumatic pain, renal colic,cancer pain and back pain. Cancer pain can be chronic pain such as tumorrelated pain (e. g., bone pain, headache, facial pain or visceral pain)or pain associated with cancer therapy (e.g., post-chemotherapysyndrome, chronic postsurgical pain syndrome or post radiationsyndrome). Cancer pain can also occur in response to chemotherapy,immunotherapy, hormonal therapy or radiotherapy. Back pain can be due toherniated or ruptured intervertebral discs or abnormalities of thelumber facet joints, sacroiliac joints, paraspinal muscles or theposterior longitudinal ligament.

In another embodiment, the condition related to pain is inflammatorypain. A common type of inflammatory pain is arthritic pain arising fromrheumatoid disease (such as ankylosing spondylitis) or symptomaticosteoarthritis or degenerative joint disease. Another type ofinflammatory pain is visceral pain. Visceral pain is pain associatedwith the viscera, which encompass the organs of the abdominal cavityincluding the sex organs, spleen and part of the digestive system. Painassociated with the viscera can be divided into digestive visceral painand non-digestive visceral pain. Commonly encountered gastrointestinaldisorders that cause pain include functional bowel disorder andinflammatory bowel disease. These gastrointestinal disorders include awide range of disease states that are currently only moderatelycontrolled, including, with respect to functional bowel disorder,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, andfunctional abdominal pain syndrome, and, in respect of inflammatorybowel disease, Crohn's disease, ileitis and ulcerative colitis, all ofwhich regularly produce visceral pain. Other types of visceral paininclude the pain associated with dysmenorrhea, cystitis and pancreatitisand pelvic pain.

In another embodiment, the condition related to pain results from amusculo-skeletal condition such as myalgia, fibromyalgia, spondylitis,sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism,dystrophinopathy, glycogenolysis, polymyositis and pyomyositis; heartand vascular pain, including pain caused by angina, myocardicalinfarction, mitral stenosis, pericarditis, Raynaud's phenomenon,scleredoma and skeletal muscle ischemia; head pain, such as migraine(including migraine with aura and migraine without aura), clusterheadache, tension-type headache mixed headache and headache associatedwith vascular disorders; and orofacial pain, including dental pain, oticpain, burning mouth syndrome, temporomandibular myofascial pain, andparoxysmal extreme pain disorder (PEPD); and inherited erythromelalgia(IEM).

In some embodiments, the methods comprise combination therapy, whereinthe compound(s) and/or salt(s) of the invention is/are co-administeredwith a second (or even a third, fourth, etc.) compound, such as, forexample, another therapeutic agent used to treat pain. The compound(s)and/or salt(s) of this invention can also be co-administered withtherapeutic agents other than therapeutic agents used to treat pain. Inthese co-administration embodiments, the compound(s) and/or salt(s) ofthe invention and the second, etc. therapeutic agent(s) may beadministered in a substantially simultaneous manner (e.g., or withinabout five minutes of each other), in a sequential manner, or both. Itis contemplated that such combination therapies may includeadministering one therapeutic agent multiple times between theadministrations of the other. The time period between the administrationof each agent may range from a few seconds (or less) to several hours ordays, and will depend on, for example, the properties of eachcomposition and active ingredient (e.g., potency, solubility,bioavailability, half-life, and kinetic profile), as well as thecondition of the patient. The compound(s) and/or salt(s) of thisinvention and the second, etc. therapeutic agent may also beadministered in a single formulation.

In certain embodiments, the method comprises co-administering to thesubject the compound(s) and/or salt(s) of the invention with one or morecompounds selected from the group consisting of nonsteroidalanti-inflammatory drugs (NSAIDs), opioid analgesics, barbiturates,benzodiazapines, histamine antagonists, sedatives, skeletal musclerelaxants, transient receptor potential ion channel antagonists,α-adrenergics, tricyclic antidepressants, anticonvulsants, tachykininantagonists, muscarinic antagonists, cyclooxygenase-2 selectiveinhibitors, neuroleptics, vanilloid receptor agonists, vanilloidreceptor antagonists, β-adrenergics, local anesthetics, corticosteroids,5-HT receptor agonists, 5-HT receptor antagonists, 5-HT_(2A) receptorantagonists, cholinergic analgesics, α₂δ ligands (such as gabapentin orpregabalin), cannabinoid receptor ligands, metabotropic glutamatesubtype 1 receptor antagonists, serotonin reuptake inhibitors,norepinephrine reuptake inhibitors, dual serotonin-noradrenalinereuptake inhibitors, Rho kinase inhibitors, inducible nitric oxidesynthase inhibitors, acetylcholinesterase inhibitors, prostaglandin E₂subtype 4 antagonists, leukotriene B4 antagonists, 5-lipoxygenaseinhibitors, sodium channel blockers, 5-HT₃ antagonists,N-methyl-D-aspartic acid receptor antagonists, phosphodiesterase Vinhibitors, voltage-gated calcium channel blockers (e.g., N-type andT-type), and KCNQ openers (e.g., KCNQ2/3 (K_(v)7.2/3)).

In one embodiment, the method comprises administering to the subject atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, with or without a pharmaceuticallyacceptable carrier, in combination with a second therapeutic agentselected from the group consisting of acetaminophen, NSAIDs, opioidanalgesics, and combinations thereof.

In one embodiment, the method comprises administering to the subject atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt, with or without a pharmaceuticallyacceptable carrier, in combination with one or more additionaltherapeutic agents for treating pain. In one embodiment, the additionaltherapeutic agent is selected from the group consisting ofacetaminophen, NSAIDs (such aspirin, ibuprofen, and naproxen), andopioid analgesics. In another embodiment, the additional therapeuticagent is acetaminophen. In another embodiment, the additionaltherapeutic agent is an NSAID. In another embodiment, the additionaltherapeutic agent is an opioid analgesic.

The present invention also is directed, in part, to one or morecompounds and/or salts of the invention for use in the treatment of avoltage-gated sodium channel-mediated condition, such as pain.

The present invention also is directed, in part, to one or morecompounds and/or salts of the invention, and, optionally one or moreadditional therapeutic agents, for use as a medicament. In someembodiments, the medicament is for treating pain. In another embodiment,the medicament is for treating neuropathic pain. In another embodiment,the medicament is for treating nociceptive pain. In another embodiment,the medicament is for treating inflammatory pain.

The present invention is further directed, in part, to a use of one ormore compounds and/or salts of the invention, and, optionally one ormore additional therapeutic agents to prepare a medicament. In someembodiments, the medicament is for co-administration with one or moreadditional therapeutic agents. In some embodiments, the medicament isfor treating pain. In some embodiments, the medicament is for treatingneuropathic pain. In some embodiments, the medicament is for treatingnociceptive pain. In some embodiments, the medicament is for treatinginflammatory pain.

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting pain.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat the pain ofperipheral neuropathy may be demonstrated by Faber C G, et al. AnnNeurol 2012; 72:26-39; Faber C G, et al. Proc. Natl. Acad. Sci. U.S.A.2012; 109:19444-19449.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat inflammatory andneuropathic pain may be demonstrated by McGowan E, et al. Anesth. Analg.2009; 109:951-958.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat chronicinflammatory knee pain may be demonstrated by Strickland I T, et al.European Journal of Pain 2008; 12:564-572.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat osteoarthritis maybe demonstrated by Schuelert N, et al. Arthritis Research & Therapy2012; 14:R5; Malfait, A-M, et al. Nat. Rev. Rheumatol. 2013; 9:654-664;and Staunton C A, et al. Current Pain and Headache Reports 2013; 17:378.The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat osteoarthitis andsciatic pain may be demonstrated by Reimann F, et al. Proceedings of theNational Academy of Sciences of the United States of America 2010;107:5148-5153.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt orester, or amide form. Alternatively, the compound can be administered asa pharmaceutical composition containing the compound of interest incombination with one or more pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of theinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

For treatment or prevention of disease, the total daily dose of thecompounds of this invention administered to a human or lower animal mayrange from about 0.0003 to about 100 mg/kg/day. For purposes of oraladministration, more preferable doses can be in the range of from about0.0003 to about 30 mg/kg/day. If desired, the effective daily dose canbe divided into multiple doses for purposes of administration;consequently, single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

EXAMPLES

Abbreviations: DCI for desorption chemical ionization; DMSO for dimethylsulfoxide; ESI for electrospray ionization; HPLC for high performanceliquid chromatography; LC/MS for liquid chromatography/massspectrometry; psi for pounds per square inch; and SFC for super criticalfluid chromatography.

Example 1piperazin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 1A 2-chloroquinolin-6-ol

Phosphoryl chloride (30.0 mL, 322 mmol) was slowly added to a mixture ofquinoline-2,6-diol (10.2 g, 63.2 mmol) and N,N-dimethylformamide (25 mL)at room temperature. The reaction mixture was warmed to 70° C. After 2.5h, the reaction mixture was cooled to room temperature and then to 0° C.using an ice bath. Ice and water were slowly added to the reactionmixture which was then slowly neutralized with sodium hydroxide pelletsand aqueous NaOH (1M). The pH of the reaction mixture was adjustedto >9. The mixture was extracted with ethyl acetate (3×). The combinedorganic extracts were dried with sodium sulfate, filtered, andconcentrated. The titled compound was used in the next step withoutfurther purification.

Example 1B methyl 6-hydroxyquinoline-2-carboxylate

The product from Example 1A (0.100 g, 0.557 mmol) in methanol (10 mL)was added to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂, Heraeus) (0.020 g, 0.028 mmol) and triethylamine (0.155mL, 1.114 mmol) in a 50 mL pressure bottle. The mixture was pressurizedwith carbon monoxide (60 psi), and stirred for 16 h at 100° C. The crudereaction mixture was filtered through diatomaceous earth. The filtratewas concentrated, and the residue was purified by column chromatographyon silica gel using a gradient of 0-100% ethyl acetate/dichloromethaneto yield 0.110 g (97%) of the titled compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 10.43 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 8.03-7.98 (m, 2H), 7.42(dd, J=9.0, 2.7 Hz, 1H), 7.23 (d, 2.7 Hz, 1H), 3.92 (s, 3H); MS (ESI)m/z 204.0 [M+1-1]⁺.

Example 1C methyl6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxylate

2-Fluoro-5-(trifluoromethyl)pyridine (26.7 mL, 221 mmol) was added to amixture of the product from Example 1B (30.0 g, 148 mmol), cesiumcarbonate (40.6 g, 125 mmol) and N,N-dimethylformamide (300 mL) at roomtemperature, and the reaction mixture was heated to 70° C. After 6 h,the reaction mixture was cooled to room temperature, and water was added(400 mL). The solid was collected by filtration and washed withadditional portions of water. The solid was dissolved in dichloromethaneand washed with brine. The organic phase was collected, dried withNa₂SO₄, filtered and concentrated. The residue was taken up in 5 volumesof methyl tert-butyl ether and heated to 50° C. to nearly dissolve allmaterial. To this was added 10 volumes of heptane. The mixture wasremoved from the heat and cooled to room temperature. The solids werecollected by filtration, washed with heptane, and dried. The materialwas further purified by column chromatography on silica gel using agradient of 0-20% ethyl acetate/dichloromethane to yield 46.6 g (91%) ofthe titled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (dd, J=1.7,0.8 Hz, 1H), 8.58-8.51 (m, 1H), 8.35-8.29 (m, 1H), 8.25 (d, J=9.2 Hz,1H), 8.15 (dd, J=8.4, 4.5 Hz, 1H), 7.94 (d, J=2.6 Hz, 1H), 7.77 (dt,J=7.2, 3.6 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 3.98 (d, J=4.4 Hz, 3H); MS(ESI) m/z 349.0 [M+H]⁺.

Example 1D6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxylic acid

Lithium hydroxide (9.61 g, 401 mmol) was added to a mixture of theproduct from Example 1C (46.6 g, 134 mmol), tetrahydrofuran (600 mL) andwater (200 mL) at room temperature. The reaction became thick andoverhead stirring was necessary. After 30 minutes, the reaction mixturewas acidified with 1 M HCl (500 mL), transferred to a separatory funnelwith water (500 mL) and extracted with ethyl acetate (2×500 mL). Theorganic phases were combined, dried with Na₂SO₄, filtered andconcentrated. The solid was dried overnight under vacuum at 50° C. toyield 44.55 g (100%) of the titled compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 13.49 (br s, 1H), 8.61 (d, J=1.5 Hz, 1H), 8.53 (d, J=8.6 Hz, 1H),8.31 (dd, J=8.7, 2.6 Hz, 1H), 8.23 (d, J=9.2 Hz, 1H), 8.14 (d, J=8.5 Hz,1H), 7.93 (d, J=2.6 Hz, 1H), 7.76 (dd, J=9.2, 2.7 Hz, 1H), 7.41 (d,J=8.7 Hz, 1H); MS (ESI) m/z 335.1 [M+1-1]⁺.

Example 1E

tert-butyl4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

To a mixture of the product from Example 1D (44.55 g, 133 mmol) andtert-butyl piperazine-1-carboxylate (27.3 g, 147 mmol) intetrahydrofuran (500 mL) at room temperature was added triethylamine(74.3 mL, 533 mmol) followed by a 15 minute addition of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (117 mL,200 mmol). After 15 min, water (500 mL) was added, and the mixture wasstirred for 5 minutes. Then the mixture was transferred to a separatoryfunnel with additional water (500 mL) and ethyl acetate (1 L). Theorganic phase was washed with water (500 mL), 1 M HCl (200 mL),saturated aqueous NaHCO₃ (200 mL) and brine (200 mL). The organic phasewas collected, dried with Na₂SO₄, filtered and concentrated. The residuewas concentrated from diethyl ether (2×) to provide 63.6 g (95%) of thetitled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (s, 1H), 8.49 (d,J=8.5 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H),7.89 (d, J=2.6 Hz, 1H), 7.75-7.69 (m, 2H), 7.39 (d, J=8.7 Hz, 1H),3.74-3.66 (m, 2H), 3.54-3.45 (m, 4H), 3.42-3.35 (m, 2H), 1.42 (s, 9H);MS (ESI) m/z 502.9 [M+H]⁺.

Example 1Fpiperazin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

To a solution of the product from Example 1E (63.6 g, 127 mmol) indichloromethane (300 mL) at room temperature was added trifluoroaceticacid (200 mL). The reaction mixture was stirred for 30 minutes,concentrated, taken up in dichloromethane and washed with 2.5 M NaOH.The organic phase was dried with Na₂SO₄, filtered and concentrated. Theresidue was concentrated from diethyl ether to provide a solid. Thesolid was dried in a vacuum oven at 50° C. to yield 50.65 g (99%) of thetitled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60-8.56 (m, 1H), 8.47(d, J=8.4 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H),7.88 (d, J=2.6 Hz, 1H), 7.77-7.60 (m, 2H), 7.39 (d, J=8.7 Hz, 1H),3.72-3.55 (m, 2H), 3.44-3.31 (m, 2H), 2.86-2.74 (m, 2H), 2.73-2.61 (m,2H); MS (ESI) m/z 403.1 [M+1-1]⁺.

Example 2N-(1,1-dioxidotetrahydrothiophen-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

A mixture of the product from Example 1D (1 g, 2.99 mmol),3-aminotetrahydrothiophene 1,1-dioxide hydrochloride (0.514 g, 2.99mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.706 g, 4.49 mmol),N,N-diisopropylethylamine (1.568 mL, 8.98 mmol), and dimethyl sulfoxide(14.96 mL) was stirred at room temperature for 4 h. Water was added,followed by saturated aqueous sodium bicarbonate. The mixture wasextracted with dichloromethane (3×), dried with Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel using a gradient of 0-100% ethyl acetate/dichloromethane toyield 1.00 g (73%) of the titled compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 9.30 (d, J=8.1 Hz, 1H), 8.63-8.60 (m, 1H), 8.55 (d, J=8.6 Hz, 1H),8.32 (dd, J=8.7, 2.4 Hz, 1H), 8.22 (d, J=9.2 Hz, 1H), 8.18 (d, J=8.5 Hz,1H), 7.94 (d, J=2.5 Hz, 1H), 7.77 (dd, J=9.2, 2.6 Hz, 1H), 7.41 (d,J=8.7 Hz, 1H), 4.88-4.76 (m, 1H), 3.51 (dd, J=13.1, 7.7 Hz, 1H),3.46-3.37 (m, 1H), 3.37-3.33 (m, 1H), 3.28-3.18 (m, 1H), 2.53-2.44 (m,1H), 2.43-2.30 (m, 1H); MS (ESI) m/z 452.1 [M+H]⁺.

Example 3(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 3A (1S,4S)-tert-butyl5-(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

The product from Example 1D (800 mg, 2.39 mmol) was subjected to theconditions described in Example 2, substituting (1 S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride to give the titledcompound.

Example 3B(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 3A was then subjected to the conditionsdescribed in Example 1F to give 855 mg (85%, over two steps) of thetitled compound. ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 8.61-8.58 (m,1H), 8.50-8.45 (m, 1H), 8.30 (dd, J=8.7, 2.4 Hz, 1H), 8.12 (d, J=9.1 Hz,1H), 7.94-7.83 (m, 2H), 7.74-7.69 (m, 1H), 7.39 (d, J=8.9 Hz, 1H),4.91-4.77 (m, 1H), 3.88 (dd, J=10.4, 2.1 Hz, 0.5H), 3.68-3.59 (m, 1.5H),3.52 (dd, J=11.1, 2.1 Hz, 1H), 3.38 (dd, J=14.0, 2.8 Hz, 1H), 3.11 (d,J=9.6 Hz, 1H), 2.98-2.89 (m, 1H), 1.82-1.74 (m, 1H), 1.69-1.59 (m, 1H);MS (ESI) m/z 415.2 [M+H]⁺.

Example 4N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 2 (5.0 g, 11.07 mmol) was subjected topreparative super critical fluid chromatography (SFC) to give 2.17 g ofthe titled compound as a single enantiomer (first to elute, t_(R) 4.17minutes, >99% ee). Preparative SFC was performed on a THAR/Waters SFC 80system running under SuperChrom™ software control. The preparative SFCsystem was equipped with an 8-way preparative column switcher, CO₂ pump,modifier pump, automated back pressure regulator (ABPR), UV detector,and 6-position fraction collector. The mobile phase comprised ofsupercritical CO₂ supplied by a Dewar of bone-dry non-certified CO₂pressurized to 350 psi with a modifier of methanol at a flow rate of 80g/min. UV detection was set to collect at a wavelength of 220 nm, thecolumn was at ambient temperature, and the backpressure regulator wasset to maintain 100 bar. The sample was dissolved in a 2:1 mixture ofmethanol/dichloromethane at a concentration of 50 mg/mL. The sample wasloaded into the modifier stream in 1 mL (50 mg) injections. The mobilephase was held isocratically at 40% methanol:carbon dioxide. Fractioncollection was time triggered. The instrument was fitted with aChiralcel® OJ-H column with dimensions 30 mm i.d.×250 mm length with 5μm particles.

Analytical SFC was performed on an Aurora SFC Fusion ASTM and Agilent1100 system running under Agilent ChemStation software control. The SFCsystem included a 10-way column switcher, CO₂ pump, modifier pump, oven,and backpressure regulator. The mobile phase comprised of supercriticalCO₂ supplied by a beverage-grade CO₂ cylinder with a modifier mixture ofmethanol at a flow rate of 3 mL/min. Oven temperature was at 35° C. andthe outlet pressure at 150 bar. The mobile phase gradient started with5% modifier and held it for 0.1 minutes at a flow rate of 1 mL/min, thenthe flow rate was ramped up to 3 mL/min and held for 0.4 min. Themodifier was ramped from 5% to 50% over the next 8 minutes at 3 mL/minthen held for 1 minute at 50% modifier (3 mL/min). The gradient wasramped down from 50% to 5% modifier over 0.5 min (3 mL/min). Theinstrument was fitted with a Chiralcel® OJ-H column with dimensions of4.6 mm i.d.×150 mm length with 5 μm particles.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (d, J=8.1 Hz, 1H), 8.63-8.60 (m,1H), 8.55 (d, J=8.6 Hz, 1H), 8.32 (dd, J=8.7, 2.4 Hz, 1H), 8.22 (d,J=9.2 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.77 (dd,J=9.2, 2.6 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 4.88-4.76 (m, 1H), 3.51 (dd,J=13.1, 7.7 Hz, 1H), 3.46-3.37 (m, 1H), 3.37-3.33 (m, 1H), 3.28-3.18 (m,1H), 2.53-2.44 (m, 1H), 2.43-2.30 (m, 1H); MS (ESI) m/z 452.1 [M+H]⁺.

Example 5N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 2 (5.0 g, 11.07 mmol) was subjected topreparative SFC to give 2.14 g of the titled compound as a singleenantiomer (second to elute, t_(R) 6.78 minutes, >99% ee). PreparativeSFC was performed on a THAR/Waters SFC 80 system running underSuperChrom™ software control. The preparative SFC system was equippedwith an 8-way preparative column switcher, CO₂ pump, modifier pump,automated back pressure regulator (ABPR), UV detector, and 6-positionfraction collector. The mobile phase comprised of supercritical CO₂supplied by a Dewar of bone-dry non-certified CO₂ pressurized to 350 psiwith a modifier of methanol at a flow rate of 80 g/min. UV detection wasset to collect at a wavelength of 220 nm, the column was at ambienttemperature, and the backpressure regulator was set to maintain 100 bar.The sample was dissolved in a 2:1 mixture of methanol/dichloromethane ata concentration of 50 mg/mL. The sample was loaded into the modifierstream in 1 mL (50 mg) injections. The mobile phase was heldisocratically at 40% methanol:carbon dioxide. Fraction collection wastime triggered. The instrument was fitted with a Chiralcel® OJ-H columnwith dimensions 30 mm i.d.×250 mm length with 5 μm particles.

Analytical SFC was performed on an Aurora SFC Fusion ASTM and Agilent1100 system running under Agilent ChemStation software control. The SFCsystem included a 10-way column switcher, CO₂ pump, modifier pump, oven,and backpressure regulator. The mobile phase comprised of supercriticalCO₂ supplied by a beverage-grade CO₂ cylinder with a modifier mixture ofmethanol at a flow rate of 3 mL/min. Oven temperature was at 35° C. andthe outlet pressure at 150 bar. The mobile phase gradient started with5% modifier and held it for 0.1 minutes at a flow rate of 1 mL/min, thenthe flow rate was ramped up to 3 mL/min and held for 0.4 min. Themodifier was ramped from 5% to 50% over the next 8 minutes at 3 mL/minthen held for 1 minute at 50% modifier (3 mL/min). The gradient wasramped down from 50% to 5% modifier over 0.5 min (3 mL/min). Theinstrument was fitted with a Chiralcel® OJ-H column with dimensions of4.6 mm i.d.×150 mm length with 5 μm particles.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (d, J=8.1 Hz, 1H), 8.63-8.60 (m,1H), 8.55 (d, J=8.6 Hz, 1H), 8.32 (dd, J=8.7, 2.4 Hz, 1H), 8.22 (d,J=9.2 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.77 (dd,J=9.2, 2.6 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 4.88-4.76 (m, 1H), 3.51 (dd,J=13.1, 7.7 Hz, 1H), 3.46-3.37 (m, 1H), 3.37-3.33 (m, 1H), 3.28-3.18 (m,1H), 2.53-2.44 (m, 1H), 2.43-2.30 (m, 1H). MS (ESI) m/z 452.1 [M+H]⁺.

Example 6[3-(morpholin-4-yl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (1.00 g, 2.99 mmol) was subjected to theconditions described in Example 2, substituting4-(azetidin-3-yl)morpholine hydrochloride for 3-aminotetrahydrothiophene1,1-dioxide hydrochloride and purifying the material by columnchromatography on silica gel using a gradient of 0-5% methanol/ethylacetate, to give 720 mg (53%) of the titled compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.61-8.57 (m, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.30 (dd,J=8.7, 2.6 Hz, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.89(d, J=2.6 Hz, 1H), 7.72 (dd, J=9.1, 2.7 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H),4.77 (dd, J=10.6, 7.0 Hz, 1H), 4.56 (dd, J=10.7, 4.9 Hz, 1H), 4.15 (dd,J=10.1, 7.5 Hz, 1H), 3.96 (dd, J=10.5, 4.8 Hz, 1H), 3.65-3.58 (m, 4H),3.24-3.16 (m, 1H), 2.37 (br s, 4H); MS (ESI) m/z 459.0 [M+H]⁺.

Example 71-(4-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}phenyl)ethanoneExample 7A 6-hydroxyquinoline-2-carboxylic acid

Lithium hydroxide (3.61 g, 151 mmol) was added to a mixture of theproduct from Example 1B (10.2 g, 50.2 mmol), tetrahydrofuran (200 mL)and water (70 mL) at room temperature. After 30 minutes, tetrahydrofuranwas distilled off, and the reaction mixture was acidified with 1 M HClto pH ˜1. A yellow solid precipitate was collected by filtration andwashed with water. The solid was dried overnight under vacuum at 50° C.to give the titled compound (9.4 g, 99%).

Example 7B tert-butyl4-(6-hydroxyquinoline-2-carbonyl)piperazine-1-carboxylate

A mixture of the product from Example 7A (4 g, 21.15 mmol), tert-butylpiperazine-1-carboxylate (3.94 g, 21.15 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(8.15 g, 25.4 mmol), N,N-diisopropylethylamine (9.41 mL, 52.9 mmol), andN,N-dimethylformamide (30 mL) was stirred at room temperature for 18 h.The reaction mixture was poured into brine, and the resultant whiteprecipitate was collected by filtration and washed with water. The solidwas dried overnight under vacuum at 50° C. to give the titled compound(6 g, 79%).

Example 7C tert-butyl4-{[6-(4-acetylphenoxy)quinolin-2-yl]carbonyl}piperazine-1-carb oxy late

A mixture of tert-butyl4-(6-hydroxyquinoline-2-carbonyl)piperazine-1-carboxylate (1 g, 2.80mmol), 1-(4-fluorophenyl)ethanone (0.42 mL, 4.20 mmol), and K₂CO₃ (0.77g, 5.60 mmol) in N,N-dimethylformamide (15 mL) was heated at 120° C. for16 h. The reaction mixture was cooled to room temperature, poured intobrine and extracted with ethyl acetate. The organic layer was washedwith brine (3×100 mL), dried with MgSO₄ and concentrated. The crudematerial was purified by column chromatography on silica gel using agradient of 0-100% heptane/ethyl acetate to give the titled compound(0.93 mg, 70%).

Example 7D1-(4-{[2-(piperazin-1-ylcarbonyl)quinolin-6-yl]oxy}phenyl)ethanone

The product from Example 7C (100 mg, 0.210 mmol) was subjected to theconditions described in Example 1F, substituting tert-butyl4-{[6-(4-acetylphenoxy)quinolin-2-yl]carbonyl}piperazine-1-carboxylatefor tert-butyl4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylateto give the titled compound (74.2 mg, 94%). ¹H NMR (300 MHz, DMSO-d₆) δppm 2.57 (s, 3H), 2.61-2.72 (m, 2H), 2.78 (dd, J=14.2, 9.4 Hz, 2H),3.33-3.41 (m, 2H), 3.53-3.72 (m, 2H), 7.13-7.25 (m, 2H), 7.52-7.74 (m,3H), 7.94-8.17 (m, 3H), 8.44 (d, J=8.4 Hz, 1H); MS (DCI) m/z 376.0[M+H]⁺.

Example 8(3-aminoazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 8A tert-butyl{1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-yl}carbamate

The product from Example 1D (1.10 g, 3.29 mmol) was subjected to theconditions described in Example 2, substituting tert-butylazetidin-3-ylcarbamate for 3-aminotetrahydrothiophene 1,1-dioxidehydrochloride.

Example 8B(3-aminoazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxyl}quinolin-2-yl)methanone

The product from Example 8A was then subjected to the conditionsdescribed in Example 1F to give 434 mg (32%, over two steps) of thetitled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.61-8.58 (m, 1H), 8.48(d, J=8.6 Hz, 1H), 8.31 (dd, J=8.7, 2.5 Hz, 1H), 8.14 (d, J=9.1 Hz, 1H),8.04 (d, J=8.6 Hz, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.72 (dd, J=9.1, 2.6 Hz,1H), 7.40 (d, J=8.7 Hz, 1H), 4.90-4.84 (m, 1H), 4.36-4.25 (m, 2H),3.83-3.71 (m, 2H), 2.21 (br s, 2H); MS (ESI) m/z 389.1 [M+H]⁺.

Example 9[cis-3,4-dihydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 9A2,5-dihydro-1H-pyrrol-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

A mixture of the compound from Example 1D (75 mg, 0.224 mmol),2,5-dihydro-1H-pyrrole (16 mg, 0.224 mmol), diisopropylethylamine (0.2mL, 1.122 mmol), and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU, 87 mg, 0.269 mmol) in N,N-dimethylacetamide(1.5 mL) was stirred overnight at room temperature. After this time, themixture was diluted with ethyl acetate (20 mL) and washed with water(3×5 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel chromatography (0 to 5%methanol-ethyl acetate, eluant) to afford the titled compound, 64 mg(74%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.59 (m, 1H), 8.49 (d, J=8.6 Hz,1H), 8.31 (m, 1H), 8.17 (d, J=8.9 Hz, 1H), 7.90-7.93 (m, 2H), 7.73 (m,1H), 7.40 (d, J=8.6 Hz, 1H), 5.93-6.01 (m, 2H), 4.66-4.69 (m, 2H),4.38-4.41 (m, 2H); MS (ESI⁺) m/z 386.1 [M+H]⁺.

Example 9B [cis-3,4-dihydroxypyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

A mixture of the product from Example 9A (38 mg, 0.099 mmol) inacetonitrile (4 mL) and t-butanol (1 mL) was treated withN-methylmorpholine-N-oxide (50% weight solution in water; 0.03 mL, 0.145mmol) and then osmium tetroxide (2.5% weight solution in t-butanol; 0.06mL, 4.78 nmol). The mixture stirred overnight at room temperature. Afterthis time, the reaction mixture was treated with solid sodium sulfite(230 mg) and stirred vigorously at room temperature for 1 h. The mixturewas then filtered through a pad of sodium sulfite, and the filtrate wasconcentrated in vacuo. The residue was chromatographed on silica gel (0to 10% methanol-ethyl acetate, eluant) to afford the titled compound (26mg, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.60 (m, 1H), 8.47 (d, J=8.6Hz, 1H), 8.31 (m, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H),7.85 (d, J=8.6 Hz, 1H), 7.73 (m, 1H), 7.40 (d, J=8.9 Hz, 1H), 4.96-5.01(m, 2H), 4.05-4.14 (m, 2H), 3.90 (m, 1H), 3.61-3.69 (m, 2H), 3.45 (m,1H); MS (ESI⁺)_(m)/z 420.1 [M+H]⁺.

Example 10pyrrolidin-1-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (500 mg, 1.496 mmol) was subjected to theconditions described in Example 2, substituting pyrrolidine for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride to give 552 mg(93%) of the titled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60-8.57(m, 1H), 8.46 (d, J=8.5 Hz, 1H), 8.30 (dd, J=8.7, 2.6 Hz, 1H), 8.13 (d,J=9.1 Hz, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.71 (dd,J=9.1, 2.7 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 3.76-3.69 (m, 2H), 3.61-3.54(m, 2H), 1.93-1.85 (m, 4H); MS (ESI) m/z 388.1 [M+H]⁺.

Example 11[4-(morpholin-4-yl)piperidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

A mixture of the product from Example 1D (0.1 g, 0.299 mmol),4-(piperidin-4-yl)morpholine (0.05 g, 0.299 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.144 g, 0.23 mmol), N,N-diisopropylethylamine (0.16 mL, 0.89 mmol),and N,N-dimethylformamide (1 mL) was stirred at room temperature for 18h. The reaction mixture was poured into brine and extracted with ethylacetate. The organic layer was washed with brine (3×100 mL), dried withMgSO₄ and concentrated. The crude material was purified by columnchromatography on silica gel using 10% ethanol in ethyl acetate aseluent to give the titled compound (0.122 g, 84%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.44 (qd, J=12.2, 4.2 Hz, 2H), 1.73 (d, J=12.2 Hz, 1H),1.92 (d, J=12.3 Hz, 1H), 2.48-2.56 (m, 4H), 2.90 (td, J=12.8, 2.7 Hz,1H), 3.08 (dd, J=18.4, 7.0 Hz, 1H), 3.57 (t, J=4.4 Hz, 4H), 3.73 (d,J=14.4 Hz, 1H), 4.53 (d, J=12.9 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H),7.61-7.78 (m, 2H), 7.89 (d, J=2.6 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 8.30(dd, J=8.7, 2.5 Hz, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.53-8.64 (m, 1H); MS(DCI) m/z 487.0 [M+H]⁺.

Example 12[(3R)-3-methylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 12A tert-butyl(2R)-2-methyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 1D (200 mg, 0.56 mmol) was subjected to theconditions described in Example 11, substituting (R)-tert-butyl2-methylpiperazine-1-carboxylate for 4-(piperidin-4-yl)morpholine togive the titled compound (242 mg, 74%).

Example 12B[(3R)-3-methylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 12A (200 mg, 0.38 mmol) was subjected to theconditions described in Example 1F, to give the titled compound (104 mg,64.5%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-1.11 (m, 3H), 2.57-2.91 (m,4H), 2.93-3.14 (m, 1H), 3.57 (d, J=11.2 Hz, 1H), 4.38 (d, J=11.3 Hz,1H), 7.38 (dt, J=11.6, 5.8 Hz, 1H), 7.63-7.78 (m, 2H), 7.88 (d, J=2.6Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.47 (d,J=8.3 Hz, 1H), 8.59 (dd, J=1.7, 0.8 Hz, 1H); MS (DCI) m/z 417.0 [M+H]⁺.

Example 13[(3S)-3-methylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 13A tert-butyl(2S)-2-methyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 1D (200 mg, 0.59 mmol) was subjected to theconditions described in Example 11, substituting (S)-tert-butyl2-methylpiperazine-1-carboxylate for 4-(piperidin-4-yl)morpholine togive the titled compound (232 mg, 75%).

Example 13B[(3S)-3-methylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 13A (200 mg, 0.38 mmol) was subjected to theconditions described in Example 1F, substituting tert-butyl(2S)-2-methyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylatefor tert-butyl4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylateto give the titled compound (106 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆) δppm 0.78-1.11 (m, 3H), 2.57-2.91 (m, 4H), 2.93-3.14 (m, 1H), 3.57 (d,J=11.2 Hz, 1H), 4.38 (d, J=11.3 Hz, 1H), 7.38 (dt, J=11.6, 5.8 Hz, 1H),7.63-7.78 (m, 2H), 7.88 (d, J=2.6 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 8.30(dd, J=8.7, 2.5 Hz, 1H), 8.47 (d, J=8.3 Hz, 1H), 8.59 (dd, J=1.7, 0.8Hz, 1H); MS (DCI) m/z 417.0 [M+1-1]⁺.

Example 14(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanoneExample 14A 6-{[5-(difluoromethyl)pyridin-2-]oxy}quinoline-2-carboxylicacid

To a mixture of the product from Example 1B (72.1 g, 355 mmol) andcesium carbonate (127 g, 390 mmol) in N-methyl-2-pyrrolidinone (1000 mL)at room temperature was added 2-chloro-5-(difluoromethyl)pyridine (42.3mL, 355 mmol). The reaction mixture was heated to 130° C. for 62 h. Thecrude product was a 1:1 mixture of ester and the correspondingcarboxylic acid. The reaction mixture was cooled to room temperature andtetrahydrofuran (400 mL) was added followed by lithium hydroxide hydrate(14 g, 334 mmol) in water. After 1 h, the mixture was acidified with 1 MHCl (pH ˜1), and the mixture was extracted with ethyl acetate (4000 mLtotal). The organic phases were combined and concentrated. The residuewas triturated with diethyl ether (800 mL). The solid was pulverized bystirring, collected by filtration, and dried to yield 65.1 g of thetitled compound. A second crop of material was collected from the motherliquor. The second crop was taken up in tetrahydrofuran (300 mL) andwater (200 mL) and treated with LiOH (8.0 g). After 30 minutes, thereaction mixture was processed in a similar manner as described above toyield 11.7 g of titled compound. All of the remaining acidic aqueouslayers were combined and extracted with 1:1 tetrahydrofuran/diethylether (3×400 mL). The combined organic layers were dried with Na₂SO₄,filtered and concentrated. The residue was processed in a similar manneras described above to yield 5.91 g of titled compound. A combined totalof 82.7 g (74%) of titled compound was obtained. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 13.27 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.42 (d, J=1.6 Hz,1H), 8.23 (d, J=9.2 Hz, 1H), 8.14 (dd, J=8.5, 3.2 Hz, 2H), 7.89 (d,J=2.6 Hz, 1H), 7.73 (dd, J=9.2, 2.6 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H),7.14 (t, J=55.3 Hz, 1H).

Example 14B tert-butyl4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

To a mixture of the product from Example 14A (20.52 g, 64.9 mmol) andtert-butyl piperazine-1-carboxylate (13.29 g, 71.4 mmol) intetrahydrofuran (400 mL) at room temperature was added triethylamine(36.2 mL, 260 mmol) followed by2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide [T3P®](56.8 mL, 97 mmol). After 15 minutes, water was added and stirring wascontinued for 15 minutes. The crude product was extracted with ethylacetate (3×300 mL). The organic phases were combined, washed withsaturated aqueous NaHCO₃ (1×200 mL) and brine (1×200 mL), dried withNa₂SO₄, filtered and concentrated. The residue was taken up in 300 mL ofdiethyl ether and stirred overnight to pulverize. The solid wascollected by filtration and dried to yield 26.0 g (83%) of the titledcompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.48 (d, J=8.5 Hz, 1H), 8.38(d, J=1.7 Hz, 1H), 8.15-8.08 (m, 2H), 7.85 (d, J=2.6 Hz, 1H), 7.72 (d,J=8.5 Hz, 1H), 7.69 (dd, J=9.1, 2.7 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H),7.12 (t, J=55.3 Hz, 1H), 3.74-3.66 (m, 2H), 3.54-3.44 (m, 4H), 3.42-3.36(m, 2H), 1.41 (s, 9H); MS (ESI) m/z 484.9 [M+H]⁺.

Example 14C(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanone

Trifluoroacetic acid (30 mL) was added to a solution of the product fromExample 14B (26.0 g, 53.6 mmol) in dichloromethane (30 mL) at roomtemperature. The reaction mixture was stirred for 30 minutes andconcentrated. Water (100 mL) was added followed by 2.5 M NaOH (100 mL).The aqueous mixture was extracted with ethyl acetate (2×200 mL). Theorganic phases were combined, dried with Na₂SO₄, filtered andconcentrated. The solid was dried in a vacuum oven at 50° C. to yield18.3 g (89%) of the titled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.47 (d, J=8.4 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.17-8.04 (m, 2H), 7.85(d, J=2.6 Hz, 1H), 7.68 (dd, J=8.9, 2.5 Hz, 2H), 7.32 (d, J=8.6 Hz, 1H),7.13 (t, J=55.3 Hz, 1H), 3.68-3.58 (m, 2H), 3.39-3.30 (m, 2H), 2.84-2.75(m, 2H), 2.70-2.62 (m, 2H); MS (ESI) m/z 385.1 [M+H]⁺.

Example 15N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting 4-aminotetrahydro-2H-thiopyran 1,1-dioxidefor 2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.03 (d,J=8.5 Hz, 1H), 8.62 (s, 1H), 8.53 (d, J=8.9 Hz, 1H), 8.32 (m, 1H), 8.23(d, J=9.1 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.77(m, 1H), 7.41 (d, J=8.9 Hz, 1H), 4.30 (m, 1H), 3.39-3.42 (m, 2H),3.11-3.15 (m, 2H), 2.25-2.32 (m, 2H), 2.12-2.19 (m, 2H); MS (ESI⁺) m/z466.1 [M+H]⁺.

Example 16[(3R)-3-ethylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 16A tert-butyl(2R)-2-ethyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 1D (200 mg, 0.59 mmol) was subjected to theconditions described in Example 11, substituting (R)-tert-butyl2-ethylpiperazine-1-carboxylate for 4-(piperidin-4-yl)morpholine to givethe titled compound (238 mg, 67.5%).

Example 16B[(3R)-3-ethylpiperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 16A (200 mg, 0.38 mmol) was subjected to theconditions described in Example 1F, substituting tert-butyl(2R)-2-ethyl-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylatefor tert-butyl4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylateto give the titled compound (145 mg, 85%). ¹H NMR (500 MHz, DMSO-d₆,rotamers) δ ppm 0.74 (t, J=7.5 Hz, 1.5H), 0.95 (t, J=7.5 Hz, 1.5H),1.08-1.33 (m, 1H), 1.35-1.49 (m, 1H), 2.52-2.95 (m, 4H), 2.95-3.12 (m,1H), 3.58 (d, J=13.1 Hz, 0.56H), 3.73 (d, J=12.1 Hz, 0.54H), 4.41 (dt,J=24.4, 10.6 Hz, 1H), 7.40 (dd, J=8.7, 3.7 Hz, 1H), 7.63-7.77 (m, 2H),7.89 (t, J=2.1 Hz, 1H), 8.10 (dd, J=9.1, 4.6 Hz, 1H), 8.31 (d, J=8.6 Hz,1H), 8.48 (d, J=8.4 Hz, 1H), 8.59 (s, 1H); MS (DCI) m/z 431 [M+H]⁺.

Example 17[(3R)-3-(hydroxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 17A tert-butyl(2R)-2-(hydroxymethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 1D (400 mg, 1.19 mmol) was subjected to theconditions described in Example 11, substituting (R)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate for4-(piperidin-4-yl)morpholine to give the titled compound (285 mg,44.7%).

Example 17B[(3R)-3-(hydroxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 17A (250 mg, 0.46 mmol) was subjected to theconditions described in Example 1F, substituting tert-butyl(2R)-2-(hydroxymethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylatefor tert-butyl4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylateto give the titled compound (163 mg, 80%). ¹H NMR (400 MHz, DMSO-d₆,rotamers) δ ppm 2.53-3.18 (m, 8H), 3.65 (dd, J=41.9, 12.3 Hz, 1H),4.27-4.61 (m, 1.5H), 4.76 (t, J=5.1 Hz, 0.5H), 7.39 (d, J=8.1 Hz, 1H),7.70 (ddd, J=10.4, 6.3, 1.9 Hz, 2H), 7.89 (d, J=2.6 Hz, 1H), 8.11 (d,J=9.1 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H),8.61 (d, J=17.7 Hz, 1H); MS (DCI) m/z 433 [M+H]⁺.

Example 18(3-hydroxyazetidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting azetidin-3-ol hydrochloride for2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.59 (s, 1H),8.48 (d, J=8.5 Hz, 1H), 8.30 (m, 1H), 8.16 (d, J=9.1 Hz, 1H), 8.05 (d,J=8.6 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.73 (m, 1H), 7.40 (d, J=8.6 Hz,1H), 5.76 (m, 1H), 4.91 (m, 1H), 4.56 (m, 1H), 4.47 (m, 1H), 4.34 (m,1H), 3.86 (m, 1H); MS (ESI⁺) m/z 390.1 [M+H]⁺.

Example 19piperazin-1-yl(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanoneExample 19A methyl6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxylate

5-Fluoro-2-(trifluoromethyl)pyridine (1.00 g, 6.06 mmol) was added to amixture of the product from Example 1B (1.119 g, 5.51 mmol), cesiumcarbonate (1.974 g, 6.06 mmol) and N,N-dimethylformamide (25 mL) at roomtemperature, and the reaction mixture was heated to 90° C. After 90minutes, the reaction mixture was cooled to room temperature, and waterwas added (150 mL). The solid was collected by filtration washing withadditional portions of water. The solid was dried in a vacuum oven at50° C. overnight to yield 1.726 g (90%) of the titled compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.73 (d, J=2.8 Hz, 1H), 8.52 (d, J=8.2 Hz, 1H),8.26-8.28 (m, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H),7.78-7.84 (m, 3H), 3.97 (s, 3H); MS (ESI) m/z 349.0 [M+H]⁺.

Example 19B6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxylic acid

Lithium hydroxide (202.6 mg, 8.46 mmol) was added to a mixture of theproduct from Example 19A (1.00 g, 2.87 mmol), tetrahydrofuran (15 mL)and water (5 mL) at room temperature. After 30 minutes, the reaction wasacidified with 1 M HCl (10 mL), transferred to a separatory funnel withwater (25 mL) and extracted with ethyl acetate (2×50 mL). The organicphases were combined, dried with Na₂SO₄, filtered and concentrated. Thesolid was dried overnight under vacuum at 50° C. to yield 956 mg (100%)of the titled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.71 (d, J=2.4Hz, 1H), 8.47 (d, J=8.6 Hz, 1H), 8.27 (d, J=9.8 Hz, 1H), 8.13 (d, J=8.6Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.74-7.81 (m, 3H); MS (ESI) m/z 335.1[M+1-1]⁺.

Example 19C tert-butyl4-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

To a mixture of the product from Example 19B (371 mg, 1.00 mmol) and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 146.7 mg, 1.49 mmol) in N,N-dimethylformamide (5 mL) at roomtemperature was added triethylamine (0.3 mL, 2.15 mmol) followed bytert-butyl piperazine-1-carboxylate (378.8 mg, 2.03 mmol). After 3 h,water (50 mL) was added, and the mixture was transferred to a separatoryfunnel and extracted with ethyl acetate (3×50 mL). The organic phase waswashed with brine (35 mL). The organic phase was collected, dried withMgSO₄, filtered and concentrated. The residue was purified by silica gelchromatography using a mobile phase of 50% ethylacetate/dichloromethane, R_(f)=0.40) to yield 489.3 mg (97%) of thetitled compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (d, J=2.8 Hz, 1H),8.47 (d, J=8.5 Hz, 1H), 8.15 (d, J=8.9 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H),7.71-7.78 (m, 4H), 3.68-3.71 (m, 2H), 3.47-3.49 (m, 4H), 3.37-3.40 (m,2H), 1.42 (s, 9H); MS (ESI) m/z 503.1 [M+H]⁺.

Example 19Dpiperazin-1-yl(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone

To a solution of the product from Example 19C (486.2 mg, 0.97 mmol) indichloromethane (5 mL) at room temperature was added trifluoroaceticacid (1 mL). The reaction mixture was stirred for 2 h, concentrated,taken up in 1 M NaOH (50 mL) and extracted with dichloromethane (3×50mL). The organic phase was dried with Na₂SO₄, filtered and concentratedto yield 376.6 mg (97%) of the titled compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.69 (d, J=2.4 Hz, 1H), 8.46 (d, J=8.6 Hz, 1H), 8.46 (d,J=8.6 Hz, 1H), 8.14 (d, J=8.9 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.72-7.78(m, 3H), 7.67 (d, J=8.5 Hz, 1H), 3.33-3.36 (m, 2H), 3.62-3.64 (m, 2H),2.79-2.81 (m, 2H), 2.67-2.69 (m, 2H); MS (ESI) m/z 403.1 [M+1-1]⁺.

Example 20[3-(trifluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

To a mixture of the product from Example 1D (107.9 mg, 0.323 mmol) and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 156.4 mg, 0.487 mmol) in dimethyl sulfoxide (1 mL) at roomtemperature was added triethylamine (0.1 mL, 0.72 mmol) followed by2-(trifluoromethyl)piperazine (79.5 mg, 0.518 mmol). After 3 h, themixture was diluted with methanol (1 mL) and purified by reverse phasepreparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 Å Prep-Pak®cartridge column (40 mm×100 mm) using a gradient of 10% to 100%acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flowrate of 70 mL/minute to yield 104.3 mg (69%) of the titled compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1:1 mixture of rotamers 8.57-5-61 (m, 1H),8.50 (dd, J=8.5, 4.6 Hz, 1H), 8.31 (dd, J=8.5, 2.4 Hz, 1H), 8.10 (t,J=9.0 Hz, 1H), 7.90 (t, J=2.7 Hz, 1H), 7.70-7.78 (m, 2H), 7.40 (dd,J=8.5, 3.7 Hz, 1H), 4.36 (dd, J=12.5, 3.1 Hz, 0.5H), 4.11-4.14 (m,0.5H), 4.02 (dd, J=13.3, 2.3 Hz, 0.5H), 3.03-3.64 (m, 4H), 2.67-2.90 (m,1.5H); MS (ESI) m/z 471.1 [M+H]⁺.

Example 21N-[2-(morpholin-4-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (106.2 mg, 0.318 mmol) was subjected to theconditions described in Example 20, substituting 2-morpholinoethanaminefor 2-(trifluoromethyl)piperazine, to give the titled compound (110.7mg, 78%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.90 (t, J=6.0 Hz, 1H),8.60-8.61 (m, 1H), 8.53 (d, J=8.2 Hz, 1H), 8.31 (dd, J=8.7, 2.6 Hz, 1H),8.17-8.20 (m, 2H), 7.93 (d, J=2.8 Hz, 1H), 7.76 (dd, J=9.2, 2.8 Hz, 1H),7.41 (d, J=8.9 Hz, 1H), 3.59-3.62 (m, 4H), 3.51 (q, J=6.7 Hz, 2H), 2.55(t, J=6.7 Hz, 2H), 2.45-2.47 (m, 4H); MS (ESI) m/z 447.1 [M+H]⁺.

Example 22N-(2-methoxyethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (101.6 mg, 0.304 mmol) was subjected to theconditions described in Example 20, substituting 2-methoxyethanamine for2-(trifluoromethyl)piperazine, to give the titled compound (62.6 mg,53%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.90 (t, J=6.0 Hz, 1H), 8.60-8.61(m, 1H), 8.53 (d, J=4.9 Hz, 1H), 8.60-8.61 (m, 1H), 8.54 (d, J=8.5 Hz,1H), 8.31 (dd, J=8.7, 2.6 Hz, 1H), 8.17-8.22 (m, 2H), 7.93 (d, J=2.8 Hz,1H), 7.76 (dd, J=9.2, 2.8 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 3.53-3.58 (m,4H), 3.31 (s, 3H); MS (ESI) m/z 392.1 [M+H]⁺.

Example 23N-(4,4-difluorocyclohexyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (200 mg, 0.59 mmol) was subjected to theconditions described in Example 1E, substituting4,4-difluorocyclohexanamine hydrochloride for tert-butylpiperazine-1-carboxylate to give the titled compound (72 mg, 53.3%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.71-2.22 (m, 8H), 4.07 (d, J=8.4 Hz, 1H),7.40 (d, J=8.7 Hz, 1H), 7.76 (dd, J=9.1, 2.7 Hz, 1H), 7.92 (d, J=2.6 Hz,1H), 8.19 (dd, J=23.9, 8.8 Hz, 2H), 8.32 (dd, J=8.7, 2.5 Hz, 1H), 8.53(d, J=8.5 Hz, 1H), 8.81 (d, J=8.4 Hz, 1H); MS (DCI) m/z 452 [M+H]⁺.

Example 24N-[(3S,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting(3S,4S)-3-amino-4-hydroxytetrahydrothiophene 1,1-dioxide for2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.88 (d, J=8.3Hz, 1H), 8.62 (m, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.34 (m, 1H), 8.22 (m,1H), 8.20 (m, 1H), 7.96 (d, J=2.7 Hz, 1H), 7.78 (m, 1H), 7.41 (d, J=8.8Hz, 1H), 6.30 (br, 1H), 4.80 (m, 1H), 4.63 (m, 1H), 3.39-3.59 (m, 4H);MS (ESI⁺) m/z 468.1 [M+H]⁺.

Example 25[2-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 25A tert-butyl3-(difluoromethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 1D (500 mg, 1.496 mmol) was subjected to theconditions described in Example 2, substituting tert-butyl3-(difluoromethyl)piperazine-1-carboxylate for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride.

Example 25B[2-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 25A was then subjected to the conditionsdescribed in Example IF to give 350 mg (51%, over two steps) of thetitled compound. ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ ppm 8.59 (s, 1H),8.50 (d, J=8.5 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.12 (t, J=8.9 Hz,1H), 7.90 (d, J=2.6 Hz, 1H), 7.74-7.71 (m, 1H), 7.69 (dd, J=8.5, 7.0 Hz,1H), 7.40 (dd, J=8.7, 3.7 Hz, 1H), 6.55 (tdd, J=57.0, 37.5, 6.7 Hz, 1H),4.82-4.74 (m, 0.5H), 4.43-4.34 (m, 0.5H), 4.35-4.27 (m, 0.5H), 3.56 (d,J=13.3 Hz, 0.5H), 3.39-3.34 (m, 0.5H), 3.16 (d, J=13.1 Hz, 0.5H),3.09-2.93 (m, 2H), 2.87-2.77 (m, 1H), 2.76-2.68 (m, 0.5H), 2.63-2.55 (m,1.5H); MS (ESI) m/z 453.1 [M+H]⁺.

Example 26N-[(3R,4S)-4-hydroxyoxidotetrahydrothiophen-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting(3R,4S)-3-amino-4-hydroxytetrahydrothiophene 1,1-dioxide for2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.88 (d, J=8.3Hz, 1H), 8.61 (m, 1H), 8.58 (d, J=8.2 Hz, 1H) 8.32 (m, 1H), 8.22 (m,1H), 8.20 (m, 1H), 7.95 (d, J=2.7 Hz, 1H), 7.78 (m, 1H), 7.41 (d, J=8.8Hz, 1H), 6.30 (br, 1H), 4.80 (m, 1H), 4.63 (m, 1H), 3.39-3.59 (m, 4H);MS (ESI⁺) m/z 468.1 [M+H]⁺.

Example 27(8aS)-2-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

A mixture of the product from Example 1D (100 mg, 0.299 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 148 mg, 0.389 mmol) inN,N-dimethylformamide (1.5 mL) was stirred at ambient temperature for 10minutes, and then (S)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-onehydrochloride (53 mg, 0.3 mmol) and (N,N-diisopropylethylamine (0.16 mL,0.9 mmol) were added. The mixture was stirred at room temperature foranother 2 h, CH₂Cl₂ (20 mL) and saturated aqueous NaHCO₃ (10 mL) wereadded to the reaction mixture. The water layer was extracted withCH₂Cl₂. The combined organic fractions were dried over MgSO₄, filteredand concentrated under reduced pressure. The residue was dissolved inmethanol, filtered using a syringe filter, and purified by preparativeHPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm).A gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B)was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 minlinear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min lineargradient 95-10% A). Samples were injected in 1.5 mL dimethylsulfoxide:methanol (1:1). A custom purification system was used,consisting of the following modules: Waters LC4000 preparative pump;Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT/INmodule, Alltech Varex III evaporative light-scattering detector; Gilson506C interface box; and two Gilson FC204 fraction collectors. The systemwas controlled using Waters Millennium32 software, automated using anAbbVie developed Visual Basic application for fraction collector controland fraction tracking. Fractions were collected based upon UV signalthreshold and selected fractions subsequently analyzed by flow injectionanalysis mass spectrometry using positive APCI ionization on a FinniganLCQ using 70:30 methanol:10 mM NH₄OH (aqueous) at a flow rate of 0.8mL/min. Loop-injection mass spectra were acquired using a Finnigan LCQrunning LCQ Navigator 1.2 software and a Gilson 215 liquid handler forfraction injection controlled by an AbbVie developed Visual Basicapplication. The desired fractions were collected and concentrated toyield 93 mg (68%) of the titled compound. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.29-1.63 (m, 1H) 1.67-2.03 (m, 3H) 2.85-3.22 (m, 1H) 3.33-3.55 (m,2H) 3.62-4.13 (m, 2H) 4.24-4.42 (m, 1H) 4.54-4.89 (m, 1H) 7.40 (d,J=8.85 Hz, 1H) 7.69-7.81 (m, 2H) 7.91 (d, J=2.75 Hz, 1H) 8.09-8.18 (m,1H) 8.25-8.35 (m, J=8.85, 2.14 Hz, 1H) 8.45-8.54 (m, J=8.55, 3.36 Hz,1H) 8.59 (s, 1H); MS (ESI) m/z 457.0 [M+1-1]⁺.

Example 28[4-(2-hydroxyethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (105.2 mg, 0.315 mmol) was subjected to theconditions described in Example 20, substituting2-(piperazin-1-yl)ethanol for 2-(trifluoromethyl)piperazine, to give thetitled compound (105.8 mg, 75%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.58-8.59 (m, 1H), 8.48 (d, J=8.2 Hz, 1H), 8.30 (dd, J=8.6, 2.4 Hz, 1H),8.11 (d, J=9.2 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.65-7.75 (m, 2H), 7.39(d, J=8.9 Hz, 1H), 4.43 (br s, 1H), 3.70-3.72 (m, 2H), 3.52 (t, J=6.1Hz, 2H), 3.44-3.46 (m, 2H), 2.53-2.56 (m, 2H), 2.42-2.46 (m, 6H); MS(ESI) m/z 447.1 [M+1-1]⁺.

Example 29[3-(methylsulfonyl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting 3-(methylsulfonyl)azetidine hydrochloridefor 2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.60 (m,1H), 8.52 (d, J=8.2 Hz, 1H), 8.31 (m, 1H), 8.22 (d, J=9.2 Hz, 1H), 8.09(d, J=8.5 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.75 (m, 1H), 7.41 (d, J=8.6Hz, 1H), 4.97-5.12 (m, 2H), 4.44 (m, 2H), 4.33 (m, 1H), 3.10 (s, 3H); MS(ESI⁺)_(m)/z 452.0.

Example 30N-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (200 mg, 0.59 mmol) was subjected to theconditions described in Example 11, substituting1-amino-2-methylpropan-2-ol for 4-(piperidin-4-yl)morpholine to give thetitled compound (205 mg, 85%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (d,J=6.1 Hz, 6H), 3.37 (t, J=7.3 Hz, 2H), 4.78 (s, 1H), 7.41 (d, J=8.7 Hz,1H), 7.76 (dd, J=9.1, 2.6 Hz, 1H), 7.94 (d, J=2.6 Hz, 1H), 8.22 (dd,J=8.8, 4.6 Hz, 2H), 8.32 (dd, J=8.7, 2.5 Hz, 1H), 8.56 (d, J=8.5 Hz,1H), 8.61-8.71 (m, 2H); MS (DCI) m/z 406 [M+H]⁺.

Example 31[(3R)-3-(methoxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 31A tert-butyl(2R)-2-(methoxymethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 17A (65 mg, 0.12 mmol) in toluene (0.8 mL) wastreated with sodium hydroxide (9.76 mg, 0.12 mmol), tetrabutylammoniumhydrogen sulfate (4.14 mg, 0.012 mmol) and dimethyl sulfate (0.023 mL,0.244 mmol), and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give the titled compound (60 mg, 90%).

Example 31B[(3R)-3-(methoxymethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 31A (55 mg, 0.1 mmol) was subjected to theconditions described in Example 1F, substituting tert-butyl(2R)-2-(methoxymethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylatefor tert-butyl4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylateto give the titled compound (40 mg, 89%). ¹H NMR (400 MHz, DMSO-d₆) δppm 2.54-3.23 (m, 8H), 3.33 (s, 3H), 3.52-3.74 (m, 1H), 4.27-4.51 (m,1H), 7.39 (dd, J=8.7, 3.7 Hz, 1H), 7.62-7.77 (m, 2H), 7.89 (t, J=2.1 Hz,1H), 8.10 (dd, J=9.1, 1.9 Hz, 1H), 8.30 (dd, J=8.7, 2.1 Hz, 1H), 8.47(d, J=8.5 Hz, 1H), 8.61 (d, J=20.2 Hz, 1H); MS (DCI) m/z 447 [M+H]⁺.

Example 32N-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamideExample 32AN-(tetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting tetrahydro-2H-thiopyran-4-amine for2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.79 (d, J=8.6Hz, 1H), 8.61 (m, 1H), 8.52 (d, J=8.5 Hz, 1H), 8.31 (m, 1H), 8.23 (d,J=9.2 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.75 (m,1H), 7.40 (d, J=8.9 Hz, 1H), 3.91 (m, 1H), 2.67-2.81 (m, 4H), 2.13 (m,2H), 1.83 (m, 2H); MS (ESI⁺) m/z 434.1 [M+H]⁺.

Example 32BN-(1-oxidotetrahydro-2H-thiopyran-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

A mixture of the product from Example 32A (0.415 g, 0.957 mmol) inethanol (11 mL) was cooled to −20° and was then treated with magnesium2-carboperoxybenzoate hexahydrate (MMPP; 0.474 g, 0.766 mmol). Thereaction mixture was stirred at −20° for 2.5 h and was then quenchedwith saturated aqueous sodium bicarbonate solution (10 mL). The mixturewas extracted with ethyl acetate (5×20 mL), then the combined extractswere concentrated in vacuo. The residue was taken up in ethyl acetate(˜3 mL), causing precipitation of a solid. This solid was collected byfiltration and air-dried to afford the titled compound (mixture ofdiastereomers; 0.233 g, 0.518 mmol, 54% yield). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.82-9.03 (m, 1H), 8.62 (m, 1H), 8.53 (m, 1H), 8.32 (m,1H), 8.23 (m, 1H), 8.16 (m, 1H), 7.92 (m, 1H), 7.75-7.77 (m, 1H), 7.40(m, 1H), 4.06-4.31 (m, 1H), 3.41 and 3.12 (2m, 1H), 2.97 and 2.83 (2m,3H), 1.84-2.41 (m, 4H); MS (ESI⁺)_(m)/z 450.1 [M+H]⁺.

Example 33N-[2-(dimethylamino)-2-oxoethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (29.67 g, 89.00 mmol) was subjected to theconditions described in Example 2, substituting2-amino-N,N-dimethylacetamide for 3-aminotetrahydrothiophene 1,1-dioxidehydrochloride, to give the titled compound (22.20 g, 60%). 1H NMR (400MHz, DMSO-d₆) δ ppm 8.95 (t, J=5.1 Hz, 1H), 8.68-8.50 (m, 2H), 8.32 (dd,J=8.7, 2.6 Hz, 1H), 8.21 (dd, J=8.8, 2.9 Hz, 2H), 7.95 (d, J=2.6 Hz,1H), 7.78 (dd, J=9.1, 2.7 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 4.25 (d,J=5.1 Hz, 2H), 3.04 (s, 3H), 2.91 (s, 3H); MS (ESI⁺) m/z 419.0 [M+H]⁺.

Example 34N-(cis-3-hydroxycyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (625 mg, 1.86 mmol) was subjected to theconditions described in Example 1E, substituting(cis)-3-aminocyclobutanoyl hydrochloride for tert-butylpiperazine-1-carboxylate to give the titled compound (280 mg, 37%). ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.07 (ddd, J=17.3, 8.8, 2.8 Hz, 2H), 2.61(ddd, J=9.4, 7.1, 2.9 Hz, 2H), 3.81-3.94 (m, 1H), 3.94-4.08 (m, 1H),5.10 (d, J=6.0 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.76 (dd, J=9.1, 2.6 Hz,1H), 7.92 (d, J=2.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.23 (d, J=9.1 Hz,1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 8.52 (d, J=8.5 Hz, 1H), 8.61 (s, 1H),8.92 (d, J=8.0 Hz, 1H); MS (DCI) m/z 404 [M+H]⁺.

Example 35(3-fluoropyrrolidin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (100 mg, 0.299 mmol) was subjected to theconditions described in Example 2, substituting 3-fluoropyrrolidinhydrochloride for 3-aminotetrahydrothiophene 1,1-dioxide hydrochlorideto give 105 mg (85%) of the titled compound. ¹H NMR (500 MHz, DMSO-d₆,rotamers) δ ppm 8.61-8.58 (m, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.30 (dd,J=8.7, 2.4 Hz, 1H), 8.15 (dd, J=9.0, 6.6 Hz, 1H), 7.93-7.87 (m, 2H),7.73 (dd, J=9.1, 2.3 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 5.49-5.32 (m, 1H),4.14-3.71 (m, 3.5H), 3.67-3.57 (m, 0.5H), 2.28-2.05 (m, 2H); MS (ESI)m/z 406.1 [M+H]⁺.

Example 36meso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 36A meso-tert-butyl{(1R,5S,6s)-3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamate

The product from Example 1D (258 mg, 0.772 mmol) was subjected to theconditions described in Example 2, substituting tert-butyl(1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride, to give the titledcompound (339 mg, 85%).

Example 36Bmeso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The protected from Example 36A was dissolved in dichloromethane (4 mL)under an atmosphere of nitrogen. A solution of 4 N hydrochloric acid (4mL) was added and the mixture was stirred at room temperature for twohours. The volatiles were removed under reduced pressure, and the crudematerial was diluted in dichloromethane. The organic layer was washedwith 1 N NaOH and dried over sodium sulfate. The solvents were removedunder reduced pressure, and the residue was triturated with heptane toafford the titled compound (125 mg, 26%). ¹H NMR (500 MHz, CDCl₃) δ ppm8.43 (s, 1H), 8.15 (dd, J=18.7, 8.8 Hz, 2H), 7.96 (dd, J=8.6, 2.3 Hz,1H), 7.88 (d, J=8.5 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.55 (dd, J=9.1,2.4 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 4.13 (dd, J=12.0, 8.3 Hz, 2H), 4.04(d, J=11.9 Hz, 1H), 3.69 (d, J=12.3 Hz, 1H), 2.34 (s, 1H), 1.92 (s, 2H);MS (ESI) m/z 415.0 [M+H]⁺.

Example 37N-(oxetan-2-ylmethyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (100.9 mg, 0.302 mmol) was subjected to theconditions described in Example 20, substituting oxetan-2-ylmethanaminefor 2-(trifluoromethyl)piperazine, to give the titled compound (79.1 mg,65%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.95 (t, J=6.1 Hz, 1H), 8.61-8.62(m, 1H), 8.55 (d, J=8.6 Hz, 1H), 8.31 (dd, J=8.7, 2.6 Hz, 1H), 8.18-8.23(m, 2H), 7.94 (d, J=2.4 Hz, 1H), 7.76 (dd, J=9.2, 2.4 Hz, 1H), 7.41 (d,J=8.9 Hz, 1H), 4.89-4.95 (m, 1H), 4.44-4.57 (m, 2H), 3.59-3.72 (m, 2H),2.62-2.70 (m, 2H), 2.42-2.50 (m, 1H); MS (ESI) m/z 404.1 [M+H]⁺.

Example 38N-[(2R)-2-hydroxypropyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (107.4 mg, 0.321 mmol) was subjected to theconditions described in Example 20, substituting (R)-1-aminopropan-2-olfor 2-(trifluoromethyl)piperazine, to give the titled compound (80.1 mg,64%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.76 (t, J=6.0 Hz, 1H), 8.61-8.62(m, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.31 (dd, J=8.7, 2.6 Hz, 1H), 8.18-8.22(m, 2H), 7.93 (d, J=2.8 Hz, 1H), 7.76 (dd, J=9.0, 2.6 Hz, 1H), 7.41 (d,J=8.9 Hz, 1H), 4.91 (br s, 1H), 3.83-3.91 (m, 1H), 3.40-3.47 (m, 1H),3.23-3.30 (m, 1H), 1.12 (d, J=6.1 Hz, 3H); MS (ESI) m/z 392.1 [M+H]⁺.

Example 394,7-diazaspiro[2.5]oct-7-yl(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (181 mg, 0.540 mmol) was subjected to theconditions described in Example 2, substituting4,7-diazaspiro[2.5]octane dihydrochloride for 3-aminotetrahydrothiophene1,1-dioxide hydrochloride, to give the titled compound (192 mg, 83%). ¹HNMR (500 MHz, CDCl₃) δ ppm 8.44 (bs, 1H), 8.23 (t, J=7.9 Hz, 1H), 8.15(dd, J=25.0, 9.1 Hz, 1H), 7.98 (dd, J=8.6, 2.5 Hz, 1H), 7.76 (dd, J=8.4,4.8 Hz, 1H), 7.63 (dd, J=5.7, 2.5 Hz, 1H), 7.61-7.53 (m, 1H), 7.15 (dd,J=8.6, 3.6 Hz, 1H), 3.88 (t, J=4.9 Hz, 1H), 3.76-3.68 (m, 2H), 3.54 (s,1H), 3.13 (t, J=5.0 Hz, 1H), 3.02 (t, J=4.8 Hz, 1H), 0.80-0.69 (m, 2H),0.69-0.63 (m, 1H), 0.54-0.49 (m, 1H); MS (ESI) m/z 429.1 [M+H]⁺.

Example 40N-(2-oxopiperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (100 mg, 0.299 mmol) was subjected to theconditions described in Example 2, substituting 4-aminopiperidin-2-one2,2,2-trifluoroacetate for 3-aminotetrahydrothiophene 1,1-dioxidehydrochloride and collecting the product by filtration after theaddition of water to give 122 mg (93%) of the titled compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.89 (d, J=8.1 Hz, 1H), 8.63-8.60 (m, 1H), 8.54(d, J=8.6 Hz, 1H), 8.31 (dd, J=8.7, 2.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H),8.17 (d, J=8.5 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 7.76 (dd, J=9.1, 2.6 Hz,1H), 7.60 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.34-4.24 (m, 1H), 3.26-3.20(m, 2H), 2.55-2.42 (m, 2H), 2.04-1.96 (m, 1H), 1.95-1.83 (m, 1H); MS(ESI) m/z 431.0 [M+H]⁺.

Example 41N-(cis-3-methoxycyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting cis-3-methoxycyclobutanamine hydrochloridefor 2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.05 (d,J=8.2 Hz, 1H), 8.61 (m, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.31 (m, 1H), 8.22(d, J=9.1 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.76(m, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.11 (m, 1H), 3.66 (m, 1H), 3.17 (s,3H), 2.58-2.67 (m, 2H), 2.09-2.17 (m, 2H); MS (ESI⁺) m/z 418.1 [M+H]⁺.

Example 42N-[2-(dimethylamino)-2-oxoethyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide

The product from Example 19B (144 mg, 0.431 mmol) was subjected to theconditions described in Example 2, substituting2-amino-N,N-dimethylacetamide hydrochloride for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride, to give the titledcompound (75 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.93 (t, J=5.1Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.21 (dd,J=20.0, 8.7 Hz, 2H), 7.98 (d, J=8.6 Hz, 1H), 7.85-7.76 (m, 3H), 4.24 (d,J=5.1 Hz, 2H), 3.03 (s, 3H), 2.91 (s, 3H); MS (ESI) m/z 419.0 [M+H]⁺.

Example 43(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3S)-3-methylpiperazin-1-yl]methanoneExample 43A tert-butyl(2S)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-methylpiperazine-1-carboxylate

The product from Example 14A (200 mg, 0.632 mmol) was subjected to theconditions described in Example 14B, substituting (S)-tert-butyl2-methylpiperazine-1-carboxylate for tert-butyl piperazine-1-carboxylateto give 155 mg (49%) of the titled compound.

Example 43B(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3S)-3-methylpiperazin-1-yl]methanone

The product from Example 43A (130 mg, 0.26 mmol) was subjected to theconditions described in Example 14C to give 100 mg (96%) of the titledcompound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69-1.13 (m, 3H), 2.30-2.46(m, 1H), 2.55-3.13 (m, 5H), 3.47-3.67 (m, 1H), 4.29-4.50 (m, 1H), 7.12(t, J=55.3 Hz, 1H), 7.32 (dd, J=8.6, 2.3 Hz, 1H), 7.57-7.74 (m, 2H),7.84 (d, J=2.5 Hz, 1H), 8.11 (dd, J=15.5, 8.9 Hz, 2H), 8.39 (d, J=1.2Hz, 1H), 8.46 (d, J=8.5 Hz, 1H); MS (DCI) m/z 399 [M+H]⁺.

Example 44N-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (600 mg, 1.79 mmol) was subjected to theconditions described in Example 2, substituting2-amino-1-(pyrrolidin-1-yl)ethanone hydrochloride for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride to give 560 mg(70%) of the titled compound. ¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (t, J=5.2Hz, 1H), 8.64-8.59 (m, 1H), 8.56 (d, J=8.5 Hz, 1H), 8.31 (dd, J=8.8, 2.6Hz, 1H), 8.20 (dd, J=8.8, 4.1 Hz, 2H), 7.95 (d, J=2.6 Hz, 1H), 7.77 (dd,J=9.2, 2.6 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 4.17 (d, J=5.1 Hz, 2H), 3.49(t, J=6.8 Hz, 2H), 3.37 (t, J=6.9 Hz, 2H), 1.93 (p, J=6.8 Hz, 2H), 1.81(p, J=6.9 Hz, 2H); MS (ESI) m/z 445.0 [M+H]⁺.

Example 45N-(1-ethyl-5-oxopyrrolidin-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (398 mg, 1.19 mmol) was subjected to theconditions described in Example 2, substituting4-amino-1-ethylpyrrolidin-2-one hydrochloride for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride, to give the titledcompound (394 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.47-8.39 (m, 2H),8.29 (s, 2H), 8.19 (d, J=9.1 Hz, 1H), 7.99 (dd, J=8.6, 2.5 Hz, 1H), 7.67(d, J=2.5 Hz, 1H), 7.61 (dd, J=9.1, 2.5 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H),4.88-4.78 (m, 1H), 3.90 (dd, J=10.4, 6.8 Hz, 1H), 3.50-3.35 (m, 3H),2.95 (dd, J=17.1, 8.3 Hz, 1H), 2.55 (dd, J=17.1, 4.6 Hz, 1H), 1.17 (t,J=7.2 Hz, 3H); MS (ESI) m/z 445.0 [M+H]⁺.

Example 466-{[5-(difluoromethyl)pyridin-2-yl]oxy}-N-(1-ethyl-5-oxopyrrolidin-3-yl)quinoline-2-carboxamide

The product from Example 14A (553 mg, 1.75 mmol) was subjected to theconditions described in Example 2, substituting4-amino-1-ethylpyrrolidin-2-one hydrochloride for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride, to give the titledcompound (651 mg, 87%). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.50-8.43 (m, 1H),8.29 (s, 3H), 8.20 (d, J=9.1 Hz, 1H), 7.94 (dd, J=8.6, 2.4 Hz, 1H), 7.66(d, J=2.5 Hz, 1H), 7.62 (dd, J=9.0, 2.6 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H),4.89-4.77 (m, 1H), 3.90 (dd, J=10.4, 6.8 Hz, 1H), 3.51-3.34 (m, 3H),2.94 (dd, J=17.1, 8.3 Hz, 1H), 2.56 (dd, J=17.1, 4.7 Hz, 1H), 1.75 (bs,1H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z 427.1 [M+H]⁺.

Example 47(4-cyclobutylpiperazin-1-yl)(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

To a mixture of the product from Example 1D (102.7 mg, 0.307 mmol) and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 157.1 mg, 0.489 mmol) in dimethyl sulfoxide (1 mL) at roomtemperature was added triethylamine (0.1 mL, 0.72 mmol) followed by1-cyclobutylpiperazine (79.4 mg, 0.566 mmol). After 3 h, the mixture wasdiluted with methanol (1 mL) and purified by reverse phase preparativeHPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA™ column (30 mm×75 mm).A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water(B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A,0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A,10.0-12.0 minutes linear gradient 95-10% A) to yield 173.9 mg (83%) ofthe titled compound as a trifluoroacetic acid salt. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.15 (br s, 1H), 8.58-8.59 (m, 1H), 8.53 (d, J=8.5 Hz,1H), 8.32 (dd, J=8.7, 2.6 Hz, 1H), 8.12 (d, J=9.2 Hz, 1H), 7.92 (d,J=2.4 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.75 (d, J=9.2, 2.7 Hz, 1H), 7.41(d, J=8.9 Hz, 1H), 4.71-7.68 (m, 1H), 4.28-4.30 (m, 1H), 3.75-3.78 (m,1H), 3.48-3.54 (m, 2H), 3.34-3.36 (m, 1H), 3.22-3.27 (m, 1H), 3.00-3.03(m, 2H), 2.20-2.23 (m, 4H), 1.71-1.82 (m, 2H); MS (ESI) m/z 457.1[M+H]⁺.

Example 48N-(3-methyloxetan-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting 3-methyloxetan-3-amine for2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.40 (s, 1H),8.62 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.31 (m, 1H), 8.21 (d, J=9.2 Hz,1H), 8.14 (d, J=8.5 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 7.77 (m, 1H), 7.41(d, J=8.5 Hz, 1H), 4.82 (d, J=6.4 Hz, 2H), 4.42 (d, J=6.4 Hz, 2H), 1.67(s, 3H); MS (ESI) m/z 404.1 [M+H]⁺.

Example 49meso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanoneExample 49 Å meso-tert-butyl{(1R,5S,6s)-3-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamate

The product from Example 14A (511 mg, 1.62 mmol) was subjected to theconditions described in Example 2, substituting meso-tert-butyl(1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride, to give the titledcompound (686 mg, 90%).

Example 49Bmeso-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl](6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 49A was dissolved in dichloromethane (4 mL)under an atmosphere of nitrogen. A solution of 4 N hydrochloric acid (4mL) was added, and the mixture was stirred at room temperature for twohours. The volatiles were removed under reduced pressure, and the crudematerial was diluted in dichloromethane. The organic layer was washedwith 1 N NaOH and dried over sodium sulfate. The solvents were removedunder reduced pressure, and the residue was triturated with heptane toafford the titled compound (307 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ ppm8.30 (d, J=2.2 Hz, 1H), 8.16 (dd, J=15.2, 8.8 Hz, 2H), 7.99-7.84 (m,2H), 7.60 (d, J=2.6 Hz, 1H), 7.56 (dd, J=9.0, 2.6 Hz, 1H), 7.12 (d,J=8.5 Hz, 1H), 6.68 (t, J=55.9 Hz, 1H), 4.28-3.99 (m, 3H), 3.71 (dd,J=12.2, 2.8 Hz, 1H), 2.88-2.06 (m, 2H), 2.28-2.21 (m, 1H); MS (ESI) m/z397.0 [M+H]⁺.

Example 50[(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (800 mg, 2.39 mmol) was subjected to theconditions described in Example 2, substituting[(2S,4S)-4fluoropyrrolidin-2-yl]methanol hydrochloride for3-aminotetrahydrothiophene 1,1-dioxide hydrochloride to give 885 mg(83%) of the titled compound. ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm8.61-8.57 (m, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H),8.16 (t, J=9.6 Hz, 1H), 7.91-7.80 (m, 2H), 7.72 (dd, J=9.1, 2.6 Hz, 1H),7.40 (d, J=8.8 Hz, 1H), 5.52-5.25 (m, 1H), 4.96 (dd, J=6.2, 5.3 Hz,0.5H), 4.83-4.72 (m, 1H), 4.41 (td, J=8.8, 4.6 Hz, 0.5H), 4.27 (dd,J=25.3, 13.7 Hz, 0.5H), 4.12-3.88 (m, 1.5H), 3.80 (dd, J=27.3, 14.9 Hz,0.5H), 3.48-3.34 (m, 1H), 3.30-3.21 (m, 0.5H), 2.43-2.09 (m, 2H); MS(ESI) m/z 436.0 [M+H]⁺.

Example 51

[(3S)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (1.0 g, 2.99 mmol) was subjected to theconditions described in Example 2, substituting (S)-3-fluoropyrrolidinehydrochloride for 3-aminotetrahydrothiophene 1,1-dioxide hydrochlorideto give 1.18 g (96%) of the titled compound. ¹H NMR (500 MHz, DMSO-d₆,rotamers) δ ppm 8.61-8.58 (m, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.30 (dd,J=8.7, 2.4 Hz, 1H), 8.15 (dd, J=9.0, 6.6 Hz, 1H), 7.93-7.87 (m, 2H),7.73 (dd, J=9.1, 2.3 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 5.49-5.32 (m, 1H),4.14-3.71 (m, 3.5H), 3.67-3.57 (m, 0.5H), 2.28-2.05 (m, 2H); MS (ESI)m/z 406.1 [M+H]⁺.

Example 52[(3R)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

A mixture of the product from Example 1D (1.0 g, 2.99 mmol),(R)-3-fluoropyrrolidine hydrochloride (0.376 g, 2.99 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 1.706 g, 4.49 mmol),N,N-diisopropylethylamine (1.568 mL, 8.98 mmol), and dimethyl sulfoxide(14.96 mL) was stirred at room temperature for 16 hours. Water wasadded, followed by saturated aqueous sodium bicarbonate. The crudeproduct was extracted with dichloromethane (3×), dried with sodiumsulfate, decanted, and concentrated. The compound was purified bychromatography on silica gel (0-100% ethyl acetate/heptanes) to give1.12 g (91%) of the titled compound. ¹H NMR (500 MHz, DMSO-d₆, rotamers)δ ppm 8.61-8.58 (m, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.30 (dd, J=8.7, 2.4Hz, 1H), 8.15 (dd, J=9.0, 6.6 Hz, 1H), 7.93-7.87 (m, 2H), 7.73 (dd,J=9.1, 2.3 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 5.49-5.32 (m, 1H), 4.14-3.71(m, 3.5H), 3.67-3.57 (m, 0.5H), 2.28-2.05 (m, 2H); MS (ESI) m/z 406.1[M+H]⁺.

Example 53[(8aS)-7,7-difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (100 mg, 0.299 mmol) was subjected to theconditions described in Example 27, substituting(S)-7,7-difluorooctahydropyrrolo[1,2-a]pyrazine dihydrochloride (91 mg,0.389 mmol) for (S)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-onehydrochloride, to give the titled compound (123 mg, 86%). ¹H NMR (400MHz, DMSO-d₆) ppm 1.77-2.10 (m, 1H) 2.17-2.49 (m, 3H) 2.53-2.67 (m, 1H)2.70-2.92 (m, 1H) 2.98-3.30 (m, 2H) 3.38-3.49 (m, 1H) 3.84 (dd, J=65.61,12.82 Hz, 1H) 4.64 (dd, J=60.73, 12.82 Hz, 1H) 7.39 (d, J=8.85 Hz, 1H)7.66-7.75 (m, 2H) 7.89 (d, J=1.83 Hz, 1H) 8.12 (dd, J=9.16, 1.83 Hz, 1H)8.31 (dd, J=8.85, 2.44 Hz, 1H) 8.49 (d, J=7.93 Hz, 1H) 8.58 (s, 1H); MS(ESI) m/z 479.0 [M+H]⁺.

Example 54N-[1-(4-fluorophenyl)-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (100 mg, 0.299 mmol) was subjected to theconditions described in Example 27, substituting4-amino-1-(4-fluorophenyl)pyrrolidin-2-one hydrochloride (69.0 mg, 0.299mmol for (S)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one hydrochloride, togive the titled compound (110 mg, 72.0%). ¹H NMR (400 MHz, DMSO-d₆) ppm2.82 (dd, J=17.09, 5.49 Hz, 1H) 2.98 (dd, J=17.09, 8.85 Hz, 1H) 3.93(dd, J=9.92, 4.73 Hz, 1H) 4.23 (dd, J=10.07, 7.63 Hz, 1H) 4.77-4.88 (m,1H) 7.23 (t, J=8.85 Hz, 2H) 7.41 (d, J=8.54 Hz, 1H) 7.70-7.81 (m, 3H)7.93 (d, J=2.75 Hz, 1H) 8.18 (d, J=8.54 Hz, 1H) 8.22 (d, J=9.16 Hz, 1H)8.31 (dd, J=8.54, 2.44 Hz, 1H) 8.54 (d, J=8.54 Hz, 1H) 8.61 (s, 1H) 9.44(d, J=7.32 Hz, 1H); MS (ESI) m/z 511 [M+H]⁺.

Example 55(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3R)-3-ethylpiperazin-1-yl]methanoneExample 55A tert-butyl(2R)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-ethylpiperazine-1-carboxylate

The product from Example 14A (300 mg, 0.95 mmol) was subjected to theconditions described in Example 14B, substituting (R)-tert-butyl2-ethylpiperazine-1-carboxylate for tert-butyl piperazine-1-carboxylateto give the titled compound (470 mg, 97%).

Example 55B(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3R)-3-ethylpiperazin-1-yl]methanone

The product from Example 55A (455 mg, 0.88 mmol) was subjected to theconditions described in Example 14C, to give the titled compound (320mg, 87%). ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 0.74 (t, J=7.5 Hz,1.5H), 0.95 (t, J=7.5 Hz, 1.5H), 1.06-1.32 (m, 1H), 1.32-1.57 (m, 1H),2.35 (s, 1H), 2.56-2.94 (m, 3H), 2.94-3.15 (m, 1H), 3.65 (dd, J=58.1,12.6 Hz, 1H), 4.40 (dd, J=26.1, 11.1 Hz, 1H), 7.12 (t, J=55.3 Hz, 1H),7.32 (dd, J=8.6, 2.6 Hz, 1H), 7.68 (ddd, J=8.3, 6.3, 2.1 Hz, 2H), 7.84(d, J=2.2 Hz, 1H), 8.01-8.22 (m, 2H), 8.39 (s, 1H), 8.46 (d, J=8.5 Hz,1H); MS (DCI) m/z 413 [M+H]⁺.

Example 56N-(2-methoxyethyl)-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxamide

The product from Example 19B (99.9 mg, 0.299 mmol) was subjected to theconditions described in Example 20, substituting 2-methoxyethanamine for2-(trifluoromethyl)piperazine, to give the titled compound (66.4 mg,57%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.85 (t, J=4.9 Hz, 1H), 8.71 (d,J=2.8 Hz, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.24 (d, J=9.2 Hz, 1H), 8.17 (d,J=8.5 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H), 7.76-7.82 (m, 3H), 3.52-3.58 (m,4H), 3.30 (s, 3H); MS (ESI) m/z 392.1 [M+H]⁺.

Example 57(6-{[5-(difluoromethoxy)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanoneExample 57A

tert-butyl4-[(6-{[5-(difluoromethoxy)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The product from Example 7B (400 mg, 1.11 mmol) was subjected to theconditions described in Example 7C, substituting2-chloro-5-(difluromethoxy)pyridine for 1-(4-fluorophenyl)ethanone at140° C. to give the titled compound (135 mg, 24%).

Example 57B(6-{[5-(difluoromethoxy)pyridin-2-yl]oxy}quinolin-2-yl)(piperazin-1-yl)methanone

The product from Example 57A (114 mg, 0.22 mmol) was subjected to theconditions described in Example 1F, to give the titled compound (76 mg,83%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (dd, J=16.6, 11.8 Hz, 2H),2.74-2.85 (m, 2H), 3.34 (d, J=14.0 Hz, 2H), 3.55-3.70 (m, 2H), 7.01-7.49(m, 2H), 7.57-7.70 (m, 2H), 7.77 (d, J=2.6 Hz, 1H), 7.84 (dd, J=8.9, 3.0Hz, 1H), 8.09 (dd, J=12.0, 6.0 Hz, 2H), 8.44 (d, J=8.5 Hz, 1H); MS (DCI)m/z 401 [M+H]⁺.

Example 58N-[(3R)-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (100 mg, 0.299 mmol) was subjected to theconditions described in Example 27, substituting(R)-4-aminopyrrolidin-2-one (35.9 mg, 0.359 mmol) for(S)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one hydrochloride, to give thetitled compound (72 mg, 57.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.44-2.58 (m, 2H) 3.26-3.32 (m, 1H) 3.61 (dd, J=9.31, 8.09 Hz, 1H)4.66-4.78 (m, 1H) 7.41 (d, J=8.85 Hz, 1H) 7.70 (s, 1H) 7.76 (dd, J=9.16,2.75 Hz, 1H) 7.93 (d, J=2.75 Hz, 1H) 8.16 (d, J=8.54 Hz, 1H) 8.23 (d,J=9.16 Hz, 1H) 8.32 (dd, J=8.54, 2.44 Hz, 1H) 8.54 (d, J=8.54 Hz, 1H)8.62 (s, 1H) 9.19 (d, J=7.63 Hz, 1H); MS (ESI) m/z 417.0 [M+H]⁺.

Example 59N-(3,3-difluorocyclobutyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (200 mg, 0.59 mmol) was subjected to theconditions described in Example 1E, substituting3,3-difluorocyclobutanamine hydrochloride for 4 tert-butylpiperazine-1-carboxylate to give the titled compound (136 mg, 53.7%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.85-3.12 (m, 4H), 4.29-4.52 (m, 1H), 7.41(d, J=8.7 Hz, 1H), 7.77 (dd, J=9.1, 2.6 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H),8.16 (d, J=8.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 8.32 (dd, J=8.7, 2.5 Hz,1H), 8.54 (d, J=8.6 Hz, 1H), 8.62 (d, J=1.3 Hz, 1H), 9.41 (d, J=7.5 Hz,1H); MS (DCI) m/z 424 [M+H]⁺.

Example 60[3-(methoxymethyl)azetidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting 3-(methoxymethyl)azetidine2,2,2-trifluoroacetate for 2,5-dihydro-1H-pyrrole. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.60 (m, 1H), 8.48 (d, J=8.8 Hz, 1H), 8.31 (m, 1H), 8.15(d, J=9.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.72(m, 1H), 7.40 (d, J=8.6 Hz, 1H), 4.80 (t, J=8.9 Hz, 1H), 4.47 (m, 1H),4.18 (t, J=9.3 Hz, 1H), 3.85 (m, 1H), 3.55 (d, J=6.4 Hz, 2H), 3.31 (s,3H), 2.93 (m, 1H); MS (ESI⁺) m/z 418.1 [M+H]⁺.

Example 61N-ethyl-N-(1-ethyl-2-oxopiperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

Sodium hydride (0.102 g, 2.56 mmol, 60% dispersion in mineral oil) wasadded to a mixture ofN-(2-oxopiperidin-4-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide(the product from Example 40) (0.5 g, 1.162 mmol), andN,N-dimethylformamide (5.81 mL) at 0° C., and the reaction mixture wasstirred for 30 minutes at 0° C. Iodoethane (0.207 mL, 2.56 mmol) wasadded. The reaction mixture was allowed to warm to room temperature andwas stirred at room temperature overnight. The reaction mixture wascooled to 0° C. using an ice bath. Water and saturated aqueous sodiumbicarbonate were added slowly. The mixture was extracted withdichloromethane (3×), dried with Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica gel using agradient of 0-100% ethyl acetate/heptanes to yield 280 mg (49%) of thetitled compound. ¹H NMR (400 MHz, CDCl₃, rotamers) δ ppm 8.44 (s, 1H),8.33-8.25 (m, 0.5H), 8.25-8.10 (m, 2H), 8.01-7.94 (m, 1H), 7.76-7.65 (m,1H), 7.64-7.54 (m, 1.5H), 7.15 (d, J=8.6 Hz, 1H), 4.69-4.32 (m, 1H),3.71 (q, J=7.0 Hz, 1H), 3.59-3.35 (m, 4H), 3.35-3.09 (m, 1H), 2.95-2.72(m, 1H), 2.69-2.47 (m, 0.5H), 2.39-2.17 (m, 1H), 2.12-1.99 (m, 0.5H),1.38 (t, J=7.0 Hz, 1H), 1.28-1.12 (m, 5H), 1.06 (t, J=7.1 Hz, 1H); MS(ESI) m/z 487.0 [M+H]⁺.

Example 62[(3R)-3-methylpiperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanoneExample 62A tert-butyl(2R)-2-methyl-4-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The titled compound was prepared using the reaction conditions describedfor Example 1E, substituting6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxylic acid for6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxylic acid and(R)-tert-butyl 2-methylpiperazine-1-carboxylate for tert-butylpiperazine-1-carboxylate (254 mg, 82%).

Example 62B[(3R)-3-methylpiperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone

The product from Example 62A (234 mg, 0.45 mmol) was subjected to theconditions described in Example 19D to give the titled compound (0.187g, 99%). ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 0.84 (d, J=5.7 Hz,1.5H), 1.05 (d, J=6.2 Hz, 1.5H), 2.56-2.91 (m, 4H), 2.93-3.12 (m, 1H),3.57 (d, J=10.8 Hz, 1H), 4.38 (d, J=12.4 Hz, 1H), 7.63-7.84 (m, 4H),7.96 (t, J=7.9 Hz, 1H), 8.14 (d, J=9.1 Hz, 1H), 8.45 (d, J=8.5 Hz, 1H),8.70 (s, 1H); MS (DCI) m/z 417 [M+H]⁺.

Example 63[(3R)-3-(methoxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanoneExample 63A tert-butyl(2R)-2-(hydroxymethyl)-4-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 1E, substituting6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxylic acid (300mg, 0.898 mmol) for6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxylic acid and(R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate for tert-butylpiperazine-1-carboxylate (402 mg, 84%).

Example 63B tert-butyl(2R)-2-(methoxymethyl)-4-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 31A, substituting (R)-tert-butyl2-(hydroxymethyl)-4-(6-((6-(trifluoromethyl)pyridin-3-yl)oxy)quinoline-2-carbonyl)piperazine-1-carboxylate(323 mg, 0.607 mmol) for tert-butyl(2R)-2-(hydroxymethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate(225 mg, 68%).

Example 63C[(3R)-3-(methoxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone

The product from Example 63B (210 mg, 0.38 mmol) was subjected to theconditions described in Example 19D, to give the titled compound (155mg, 90%). ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 2.55-3.24 (m, 8H),3.33 (dd, J=12.0, 5.0 Hz, 3H), 3.51-3.73 (m, 1H), 4.24-4.39 (m, 0.514),4.39-4.53 (m, 0.5H), 7.59-7.85 (m, 4H), 7.97 (d, J=8.7 Hz, 1H),8.07-8.20 (m, 1H), 8.46 (d, J=8.5 Hz, 1H), 8.64-8.76 (m, 1H); MS (DCI)m/z 447 [M+H]⁺.

Example 64[(3S)-3-(methoxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanoneExample 64A tert-butyl(2S)-2-(hydroxymethyl)-4-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 1E, substituting6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinoline-2-carboxylic acid (300mg, 0.898 mmol) for6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxylic acid and(S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate fortert-butylpiperazine-1-carboxylate (422 mg, 79%).

Example 64B tert-butyl(2S)-2-(methoxymethyl)-4-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 31A, substituting (S)-tert-butyl2-(hydroxymethyl)-4-(6-((6-(trifluoromethyl)pyridin-3-yl)oxy)quinoline-2-carbonyl)piperazine-1-carboxylate(345 mg, 0.648 mmol) for tert-butyl(2R)-2-(hydroxymethyl)-4-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]piperazine-1-carboxylate(226 mg, 64%)

Example 64C[(3S)-3-(methoxymethyl)piperazin-1-yl](6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone

The product from Example 64B (210 mg, 0.38 mmol) was subjected to theconditions described in Example 1F, to give the titled compound (152 mg,89%). ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 2.55-3.24 (m, 8H), 3.33(dd, J=12.0, 5.0 Hz, 3H), 3.51-3.73 (m, 1H), 4.24-4.39 (m, 0.514),4.39-4.53 (m, 0.5H), 7.59-7.85 (m, 4H), 7.97 (d, J=8.7 Hz, 1H),8.07-8.20 (m, 1H), 8.46 (d, J=8.5 Hz, 1H), 8.64-8.76 (m, 1H); MS (DCI)m/z 447 [M+H]⁺.

Example 65N-[3-(methylsulfonyl)propyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was prepared using the reaction conditions describedfor Example 9A, substituting 3-(methylsulfonyl)propan-1-amine (preparedaccording to WO2007127183, Example 308) for 2,5-dihydro-1H-pyrrole. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 9.12 (t, J=6.1 Hz, 1H), 8.61 (s, 1H), 8.54(d, J=8.5 Hz, 1H), 8.31 (m, 1H), 8.20 (d, J=9.1 Hz, 1H), 8.18 (d, J=8.5Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.77 (m, 1H), 7.41 (d, J=8.9 Hz, 1H),3.50 (q, J=6.7 Hz, 2H), 3.19 (m, 2H), 2.99 (s, 3H), 2.03 (m, 2H); MS(ESI⁺) m/z 454.1 [M+H]⁺.

Example 66(3-aminoazetidin-1-yl)(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanoneExample 66A tert-butyl{1-[(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-yl}carbamate

To a mixture of the product from Example 19B (461.3 mg, 1.380 mmol) and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 576.0 mg, 1.794 mmol) in dimethyl sulfoxide (3 mL) at roomtemperature was added triethylamine (0.5 mL, 3.59 mmol) followedtert-butyl azetidin-3-ylcarbamate (383.9 mg, 1.615 mmol). After 17 h, aprecipitate had formed. The reaction mixture was diluted with methanol(3 mL) and the precipitate was isolated by filtration, washed withadditional methanol (3×2 mL) and dried to yield 383.4 mg (57%) of thetitled compound.

Example 66B(3-aminoazetidin-1-yl)(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}quinolin-2-yl)methanone

The product from Example 66A (357.2 mg, 0.731 mmol) was subjected to theconditions described in Example 19D to give the titled compound (246.0mg, 87%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (d, J=2.8 Hz, 1H), 8.46(d, J=8.5 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.97(d, J=8.9 Hz, 1H), 7.73-7.80 (m, 3H), 4.85-4.89 (m, 1H), 4.26-4.34 (m,2H), 3.72-3.83 (m, 2H); MS (ESI) m/z 389.1 [M+H]⁺.

Example 67(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(3,5-dimethylpiperazin-1-yl)methanoneExample 67A tert-butyl4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2,6-dimethylpiperazine-1-carboxylate

The product from Example 14A (350 mg, 1.1 mmol) was subjected to theconditions described in Example 14B, substituting tert-butyl2,6,dimethylpiperazine-1-carboxylate for tert-butylpiperazine-1-carboxylate to give the titled compound (406 mg, 72%).

Example 67B(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)(3,5-dimethylpiperazin-1-yl)methanone

The product from Example 67A (310 mg, 0.58 mmol) was subjected to theconditions described in Example 14C, to give the titled compound (235mg, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84 (d, J=6.2 Hz, 3H), 1.06(d, J=6.3 Hz, 3H), 2.35 (dd, J=12.3, 10.8 Hz, 2H), 2.64 (dd, J=12.3,10.8 Hz, 1H), 2.68-2.88 (m, 2H), 3.58 (d, J=11.9 Hz, 1H), 4.44 (dd,J=12.4, 1.1 Hz, 1H), 7.12 (t, J=55.3 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H),7.61-7.72 (m, 2H), 7.85 (d, J=2.6 Hz, 1H), 8.01-8.20 (m, 2H), 8.39 (d,J=1.6 Hz, 1H), 8.46 (d, J=8.4 Hz, 1H); MS (DCI) m/z 413 [M+H]⁺.

Example 68(6-{[5-(difluoromethyl)pyridin-2-]oxy}quinolin-2-yl)[(3R)-3-methylpiperazin-1-yl]methanoneExample 68A tert-butyl(2R)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-methylpiperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 14B, substituting (R)-tert-butyl2-methylpiperazine-1-carboxylate for tert-butyl piperazine-1-carboxylate(269 mg, 53%).

Example 68B(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3R)-3-methylpiperazin-1-yl]methanone

The product from Example 68A (250 mg, 0.5 mmol) was subjected to theconditions described in Example 14C, to give the titled compound (172mg, 86%). ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ ppm 0.84 (d, J=5.9 Hz,1.5H), 1.05 (d, J=6.3 Hz, 1.5H), 2.27-2.40 (m, 1H), 2.40-2.49 (m, 0.5H),2.56-2.91 (m, 3.5H), 2.91-3.12 (m, 1H), 3.50-3.65 (m, 1H), 4.40 (t,J=11.8 Hz, 1H), 7.12 (t, J=55.3 Hz, 1H), 7.32 (dd, J=8.6, 3.1 Hz, 1H),7.58-7.73 (m, 2H), 7.85 (d, J=2.3 Hz, 1H), 8.11 (dd, J=19.1, 8.8 Hz,2H), 8.39 (d, J=1.0 Hz, 1H), 8.46 (d, J=8.5 Hz, 1H); MS (DCI) m/z 399[M+H]⁺.

Example 69(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3S)-3-(methoxymethyl)piperazin-1-yl]methanoneExample 69A tert-butyl(2S)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-(hydroxymethyl)piperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 14B, substituting (S)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate for tert-butylpiperazine-1-carboxylate (592 mg, 73%).

Example 69B tert-butyl(2S)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-(methoxymethyl)piperazine-1-carboxylate

The product from Example 69A (263 mg, 0.511 mmol) was subjected to theconditions described in Example 31A, to give the titled compound (209mg, 77%).

Example 69C(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3S)-3-(methoxymethyl)piperazin-1-yl]methanone

The product from Example 69B (180 mg, 0.34 mmol) was subjected to theconditions described in Example 14C, to give the titled compound (99 mg,68%). ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 2.33-3.21 (m, 10H),3.53-3.74 (m, 1H), 4.27-4.39 (m, 0.5H), 4.41-4.54 (m, 0.5H), 7.12 (t,J=55.4 Hz, 1H), 7.32 (dd, J=8.6, 3.4 Hz, 1H), 7.62-7.73 (m, 2H),7.81-7.88 (m, 1H), 8.11 (ddd, J=10.9, 8.9, 1.5 Hz, 2H), 8.39 (s, 1H),8.47 (d, J=8.6 Hz, 1H); MS (DCI) m/z 429 [M+1-1]⁺.

Example 70{3-[(3R)-3-fluoropyrrolidin-1-yl]azetidin-1-yl}(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 1D (7.65 g, 22.88 mmol) was subjected to theconditions described in Example 2, substituting azetidine-3-onehydrochloric acid for 3-aminotetrahydrothiophene 1,1-dioxidehydrochloride to give 2.73 g (31%) of1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-one.A mixture of1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]azetidin-3-one(0.2 g, 0.516 mmol), (R)-3-fluoropyrrolidine hydrochloride (0.065 g,0.516 mmol), acetic acid (0.059 mL, 1.033 mmol), and methanol (3.97 mL)was stirred at room temperature for 45 minutes. Sodium cyanoborohydrideon resin (0.5 g, 1.09 mmol, 2.17 mmol/g) was added. The reaction mixturewas stirred at room temperature for 16 h. The resin was removed byfiltration and washed with methanol. The filtrate was concentrated. Theresidue was dissolved in methanol, filtered using a syringe filter, andpurified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 ÅAXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min(0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95%A, 10.0-12.0 min linear gradient 95-10% A). Samples were injected in 1.5mL dimethyl sulfoxide:methanol (1:1). A custom purification system wasused, consisting of the following modules: Waters LC4000 preparativepump; Waters 996 diode-array detector; Waters 717+ autosampler; WatersSAT/IN module, Alltech Varex III evaporative light-scattering detector;Gilson 506C interface box; and two Gilson FC204 fraction collectors. Thesystem was controlled using Waters Millennium32 software, automatedusing an AbbVie developed Visual Basic application for fractioncollector control and fraction tracking. Fractions were collected basedupon UV signal threshold and selected fractions subsequently analyzed byflow injection analysis mass spectrometry using positive APCI ionizationon a Finnigan LCQ using 70:30 methanol:10 mM NH₄OH (aqueous) at a flowrate of 0.8 mL/min. Loop-injection mass spectra were acquired using aFinnigan LCQ running LCQ Navigator 1.2 software and a Gilson 215 liquidhandler for fraction injection controlled by an AbbVie developed VisualBasic application. The desired fractions were then combined and treatedwith saturated aqueous sodium bicarbonate. The desired material wasextracted with dichloromethane (3 x), dried with Na₂SO₄, filtered andconcentrated to yield 89 mg (37%) of the titled compound. ¹H NMR (400MHz, DMSO-d₆, rotamers) δ ppm 8.61-8.57 (m, 1H), 8.48 (d, J=8.6 Hz, 1H),8.30 (dd, J=8.7, 2.6 Hz, 1H), 8.18 (dd, J=9.1, 2.7 Hz, 1H), 8.04 (d,J=8.6 Hz, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.72 (dd, J=9.1, 2.6 Hz, 1H),7.39 (d, J=8.7 Hz, 1H), 5.33-5.28 (m, 0.5H), 5.19-5.14 (m, 0.5H),4.83-4.76 (m, 1H), 4.60-4.53 (m, 1H), 4.19 (dd, J=10.1, 7.3 Hz, 1H),4.02-3.94 (m, 1H), 3.47-3.40 (m, 1H), 2.94-2.79 (m, 2H), 2.71 (dd,J=11.5, 4.9 Hz, 0.5H), 2.63 (dd, J=11.5, 4.9 Hz, 0.5H), 2.44-2.35 (m,1H), 2.24-2.06 (m, 1H), 1.99-1.82 (m, 1H); MS (ESI) m/z 461.1 [M+H]⁺.

Example 71(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)[(3R)-3-(methoxymethyl)piperazin-1-yl]methanoneExample 71A tert-butyl(2R)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-(hydroxymethyl)piperazine-1-carboxylate

The titled compound was prepared using the conditions described inExample 14B, substituting (R)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate for tert-butylpiperazine-1-carboxylate (780 mg, 96%).

Example 71B tert-butyl(2R)-4-[(6-{[5-(difluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)carbonyl]-2-(methoxymethyl)piperazine-1-carboxylate

The product from Example 71A (215 mg, 0.418 mmol) was subjected to theconditions described in Example 31A, to give the titled compound (86 mg,39%).

Example 71C

The product from Example 71B (80 mg, 0.15 mmol) was subjected to theconditions described in Example 14C, to give the titled compound (53 mg,82%). ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 2.33-3.21 (m, 10H),3.53-3.74 (m, 1H), 4.27-4.39 (m, 0.5H), 4.41-4.54 (m, 0.5H), 7.12 (t,J=55.4 Hz, 1H), 7.32 (dd, J=8.6, 3.4 Hz, 1H), 7.62-7.73 (m, 2H),7.81-7.88 (m, 1H), 8.11 (ddd, J=10.9, 8.9, 1.5 Hz, 2H), 8.39 (s, 1H),8.47 (d, J=8.6 Hz, 1H); MS (DCI) m/z 429 [M+1-1]⁺.

Example 72[(2S*)-2-(difluoromethyl)piperazin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone

The product from Example 25B (1.39 g, 3.07 mmol) was subjected topreparative super critical fluid chromatography (SFC) to give 589 mg ofthe titled compound as a single enantiomer (second to elute, t_(R)=5.28minutes, >99% ee). Preparative SFC was performed on a THAR/Waters SFC 80system running under SuperChrom software control. The preparative SFCsystem was equipped with an 8-way preparative column switcher, CO₂ pump,modifier pump, automated back pressure regulator (ABPR), UV detector,and 6-position fraction collector. The mobile phase comprised ofsupercritical CO₂ supplied by a Dewar of bone-dry non-certified CO₂pressurized to 350 psi with a modifier of methanol buffered with 0.3%diethylamine at a flow rate of 70 g/minute. UV detection was set tocollect at a wavelength of 220 nm, the column was at ambienttemperature, and the backpressure regulator was set to maintain 100 bar.The sample was dissolved in methanol at a concentration of 40 mg/mL. Thesample was loaded into the modifier stream in 1.5 mL (40 mg) injections.The mobile phase was held isocratically at 30% methanol:CO₂. Fractioncollection was time triggered. The instrument was fitted with aCHIRALCEL® OZ-H column with dimensions 21 mm i.d.×250 mm length with 5μm particles.

Analytical SFC was performed on an Aurora A5 SFC Fusion and Agilent 1100system running under Agilent Chemstation software control. The SFCsystem included a 10-way column switcher, CO₂ pump, modifier pump, oven,and backpressure regulator. The mobile phase comprised of supercriticalCO₂ supplied by a beverage-grade CO₂ cylinder with a modifier mixture ofmethanol buffered with 0.1% diethylamine at a flow rate of 3 mL/minute.Oven temperature was at 35° C. and the outlet pressure at 150 bar. Themobile phase gradient started with 5% modifier and held it for 0.1minutes at a flow rate of 1 mL/minute, then the flow rate was ramped upto 3 mL/minute and held for 0.4 minutes. The modifier was ramped from 5%to 50% over the next 8 minutes at 3 mL/minute then held for 1 minute at50% modifier (3 mL/minute). The gradient was ramped down from 50% to 5%modifier over 0.5 minutes (3 mL/minute). The instrument was fitted witha CHIRALCEL® OZ-H column with dimensions of 4.6 mm i.d.×150 mm lengthwith 5 μm particles.

This was the second compound to elute from the SFC purification. It isan enantiopure sample, but the absolute stereochemistry was notdetermined. ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ ppm 8.59 (s, 1H), 8.50(d, J=8.5 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.12 (t, J=8.9 Hz, 1H),7.90 (d, J=2.6 Hz, 1H), 7.74-7.71 (m, 1H), 7.69 (dd, J=8.5, 7.0 Hz, 1H),7.40 (dd, J=8.7, 3.7 Hz, 1H), 6.55 (tdd, J=57.0, 37.5, 6.7 Hz, 1H),4.82-4.74 (m, 0.5H), 4.43-4.34 (m, 0.5H), 4.35-4.27 (m, 0.5H), 3.56 (d,J=13.3 Hz, 0.5H), 3.39-3.34 (m, 0.5H), 3.16 (d, J=13.1 Hz, 0.5H),3.09-2.93 (m, 2H), 2.87-2.77 (m, 1H), 2.76-2.68 (m, 0.5H), 2.63-2.55 (m,1.5H); MS (ESI) m/z 453.1 [M+H]⁺.

Example 73N-[(3R*)-1-methyl-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The product from Example 1D (500 mg, 1.5 mmol) was subjected to theconditions described in Example 27, substituting4-amino-1-methylpyrrolidin-2-one hydrochloride (225 mg, 1.496 mmol) for(S)-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one hydrochloride, to giveN-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide(460 mg, 71.5% yield), which subjected to chiral SFC separation(CHIRALCEL® OJ-H, 5-50% methanol:carbon dioxide, 10 minutes at flow rate3 mL/minute, 150 bar) to yield the titled compound (first to elute,t_(R)=3.42 minutes, >99% ee) (206 mg, 44.8%). It is an enantiopuresample, but the absolute stereochemistry was not determined ¹H NMR (400MHz, DMSO-d₆) ppm 2.52-2.72 (m, 2H) 2.77 (s, 3H) 3.41 (dd, J=10.07, 4.88Hz, 1H) 3.73 (dd, J=9.92, 7.78 Hz, 1H) 4.60-4.71 (m, 1H) 7.40 (d, J=8.85Hz, 1H) 7.76 (dd, J=9.16, 2.44 Hz, 1H) 7.93 (d, J=2.44 Hz, 1H) 8.16 (d,J=8.54 Hz, 1H) 8.22 (d, J=9.16 Hz, 1H) 8.31 (dd, J=8.70, 2.29 Hz, 1H)8.53 (d, J=8.54 Hz, 1H) 8.61 (s, 1H) 9.24 (d, J=7.32 Hz, 1H); MS (EST)m/z 431.0 [M+H]⁺.

Example 74N-[(3S*)-1-methyl-5-oxopyrrolidin-3-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide

The titled compound was obtained (second to elute, t_(R)=4.77minutes, >99% ee) (203 mg, 44.1% yield) from chiral SFC separationdescribed in Example 73. It is an enantiopure sample, but the absolutestereochemistry undetermined. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.53-2.72(m, 2H) 2.77 (s, 3H) 3.41-3.47 (m, 1H) 3.73 (dd, J=9.92, 7.78 Hz, 1H)4.60-4.73 (m, 1H) 7.40 (d, J=8.85 Hz, 1H) 7.76 (dd, J=9.16, 2.75 Hz, 1H)7.92 (d, J=2.75 Hz, 1H) 8.16 (d, J=8.54 Hz, 1H) 8.23 (d, J=9.16 Hz, 1H)8.31 (dd, J=8.85, 2.44 Hz, 1H) 8.54 (d, J=8.54 Hz, 1H) 8.61 (s, 1H) 9.25(d, J=7.32 Hz, 1H); MS (ESI) m/z 431.0 [M+H]⁺.

The compounds in the table below were prepared using methodologiesdescribed in the above Schemes and Examples. Compounds containing abasic nitrogen moiety that were purified by reverse phase HPLC using aneluent buffered with trifluoroacetic acid were isolated as thecorresponding trifluoroacetic acid salt.

Example Number Name ¹H NMR MS Example N-(3,3,3-trifluoro-2- ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.01 (t, MS 75 hydroxypropyl)-6- J = 6.0 Hz, 1H),8.61 (d, J = 2.4 Hz, 1H), (ESI) {[5- 8.56 (d, J = 8.6 Hz, 1H), 8.32 (dd,J = 8.7, 2.6 Hz, m/z (trifluoromethyl)pyridin- 1H), 8.24-8.17 (m, 2H),7.94 (d, J = 2.6 Hz, 397.0 2- 1H), 7.77 (dd, J = 9.1, 2.6 Hz, 1H), 7.41(d, J = 8.7 Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H), 6.56 (bs, 1H),4.38-4.29 (m, carboxamide 1H), 3.78-3.66 (m, 1H), 3.59-3.48 (m, 1H).Example morpholin-4-yl[6- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.58 (d, MS 76(pyridin-2- J = 8.6 Hz, 1H), 8.17-8.09 (m, 2H), 7.87 (dd, (ESI)yloxy)quinolin-2- J = 9.0, 2.4 Hz, 1H), 7.83-7.74 (m, 2H), m/zyl]methanone 7.62-7.53 (m, 1H), 6.59-6.51 (m, 1H), 6.40 (td, J = 6.7,336.1 1.3 Hz, 1H), 3.73 (s, 4H), [M + H]⁺ 3.63-3.55 (m, 2H), 3.53-3.46(m, 2H). Example (4-methylpiperazin-1- ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.56 (d, MS 77 yl)[6-(pyridin-2- J = 8.6 Hz, 1H), 8.16-8.09 (m, 2H),7.86 (dd, (ESI) yloxy)quinolin-2- J = 9.0, 2.4 Hz, 1H), 7.84-7.78 (m,1H), m/z yl]methanone 7.73 (d, J = 8.5 Hz, 1H), 7.62-7.53 (m, 1H), 349.16.55 (d, J = 8.4 Hz, 1H), 6.40 (td, J = 6.7, 1.3 Hz, [M + H]⁺ 1H),3.76-3.67 (m, 2H), 3.48-3.37 (m, 2H), 2.47-2.38 (m, 2H), 2.36-2.28 (m,2H), 2.22 (s, 3H). Example [3-(3-methyl-1,2,4- ¹H NMR (300 MHz, DMSO-d₆,rotamers) δ MS 78 oxadiazol-5- ppm 8.58 (dd, J = 8.5, 5.4 Hz, 1H), (ESI)yl)piperidin-1-yl][6- 8.16-8.07 (m, 2H), 7.90-7.79 (m, 2H), 7.74 (dd, J= 8.5, m/z (pyridin-2- 1.9 Hz, 1H), 7.62-7.54 (m, 1H), 6.55 (d, J = 9.2Hz, 416.2 yloxy)quinolin-2- 1H), 6.43-6.36 (m, 1H), [M + H]⁺yl]methanone 4.74-4.61 (m, 0.5H), 4.14-3.94 (m, 1H), 3.74-3.60 (m, 1H),3.51-3.33 (m, 2H), 3.28-3.16 (m, 0.5H), 2.37 (s, 1H), 2.25 (s, 2H),2.23-2.15 (m, 1H), 2.02-1.60 (m, 3H). Example N-[2-(piperidin-1- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.90 (t, MS 79 yl)ethyl]-6-(pyridin- J = 5.6Hz, 1H), 8.63 (d, J = 8.6 Hz, 1H), (ESI) 2-yloxy)quinoline-2- 8.25-8.16(m, 3H), 7.92 (dd, J = 9.0, 2.3 Hz, 1H), m/z carboxamide 7.86-7.81 (m,1H), 7.62-7.54 (m, 1H), 377.1 6.58-6.53 (m, 1H), 6.40 (td, J = 6.7, 1.2Hz, 1H), [M + H]⁺ 3.49 (q, J = 6.6 Hz, 2H), 2.47-2.33 (m, 6H), 1.59-1.47(m, 4H), 1.47-1.37 (m, 2H). Example 6-(pyridin-2-yloxy)- ¹H NMR (300MHz, DMSO-d₆) δ ppm MS 80 N-(1,2,4-thiadiazol-5- 13.56 (s, 1H), 8.73 (d,J = 8.7 Hz, 1H), 8.60 (s, 1H), (ESI) yl)quinoline-2- 8.34 (d, J = 8.6Hz, 2H), 8.25 (d, J = 2.3 Hz, m/z carboxamide 1H), 7.99 (dd, J = 9.0,2.4 Hz, 1H), 350.2 7.88-7.83 (m, 1H), 7.63-7.56 (m, 1H), 6.60-6.54 (m,[M + H]⁺ 1H), 6.42 (td, J = 6.7, 1.3 Hz, 1H). Example 4-({2-[(4- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.46 (d, MS 81 methylpiperazin-1- J = 8.4 Hz,1H), 8.12 (d, J = 9.1 Hz, 1H), (ESI) yl)carbonyl]quinolin- 7.93-7.87 (m,2H), 7.73 (d, J = 2.7 Hz, 1H), m/z 6-yl}oxy)benzonitrile 7.70-7.63 (m,2H), 7.29-7.23 (m, 2H), 373.1 3.75-3.67 (m, 2H), 3.48-3.40 (m, 2H), [M +H]⁺ 2.46-2.38 (m, 2H), 2.34-2.27 (m, 2H), 2.21 (s, 3H). Example6-(4-cyanophenoxy)- ¹H NMR (300 MHz, DMSO-d₆) δ ppm MS 82N-[2-(piperidin-1- 8.89-8.81 (m, 1H), 8.51 (d, J = 8.4 Hz, 1H), (ESI)yl)ethyl]quinoline-2- 8.21-8.13 (m, 2H), 7.96-7.88 (m, 2H), m/zcarboxamide 7.76-7.67 (m, 2H), 7.33-7.26 (m, 2H), 3.47 (dd, J = 12.8,401.1 6.6 Hz, 2H), 2.54-2.46 (m, 2H), [M + H]⁺ 2.45-2.38 (m, 4H),1.59-1.47 (m, 4H), 1.46-1.34 (m, 2H). Example 4-{[2-(morpholin-4- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.47 (d, MS 83 ylcarbonyl)quinolin- J = 8.5 Hz,1H), 8.13 (d, J = 9.1 Hz, 1H), (ESI) 6-yl]oxy}benzonitrile 7.94-7.88 (m,2H), 7.75-7.64 (m, 3H), m/z 7.30-7.23 (m, 2H), 3.72 (s, 4H), 3.63-3.55(m, 360.1 2H), 3.54-3.47 (m, 2H). [M + H]⁺ Example 6-(4-cyanophenoxy)-¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 84 N-(1H-indazol-6- ppm 8.55(d, J = 8.5 Hz, 1H), 8.39-8.32 (m, (APCI) yl)quinoline-2- 1H), 8.30 (d,J = 1.5 Hz, 1H), 8.27 (d, J = 8.4 Hz, m/z carboxamide 1H), 8.02 (s, 1H),7.89-7.83 (m, 2H), 406.1 7.77 (d, J = 8.6 Hz, 1H), 7.73-7.67 (m, 2H),[M + H]⁺ 7.50 (dd, J = 8.6, 1.8 Hz, 1H), 7.32-7.26 (m, 2H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 85 N-[3-ppm 8.48 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.7 Hz, (APCI)(dimethylamino)propyl]quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), m/z 2-7.91-7.80 (m, 2H), 7.71-7.61 (m, 2H), 7.31-7.21 (m, 375.0 carboxamide2H), 3.49 (t, J = 6.8 Hz, 2H), 3.19-3.12 (m, [M + H]⁺ 2H), 2.83 (s, 6H),2.08-1.92 (m, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 86 N-[2-(morpholin-4- ppm 8.49 (d, J = 8.6 Hz,1H), 8.28-8.18 (m, (APCI) yl)ethyl]quinoline-2- 1H), 8.16 (d, J = 8.5Hz, 1H), 7.91-7.80 (m, m/z carboxamide 2H), 7.67 (m, 2H), 7.32-7.21 (m,2H), 403.1 3.91-3.82 (m, 4H), 3.80 (t, J = 6.2 Hz, 2H), 3.42 (t, [M +H]⁺ J = 6.2 Hz, 2H), 3.39-3.32 (m, 4H). Example 6-(4-cyanophenoxy)- ¹HNMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 87 N-[3-(morpholin-4- ppm 8.48(d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.7 Hz, (APCI) yl)propyl]quinoline-1H), 8.15 (d, J = 8.5 Hz, 1H), m/z 2-carboxamide 7.91-7.80 (m, 2H),7.72-7.60 (m, 2H), 7.31-7.21 (m, 417.1 2H), 3.86 (s, 4H), 3.51 (t, J =6.7 Hz, 2H), [M + H]⁺ 3.26-3.15 (m, 6H), 2.13-1.99 (m, 2H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 88N-(1,3-thiazol-2- ppm 8.57 (d, J = 8.6 Hz, 1H), 8.35 (d, J = 10.0 Hz,(APCI) yl)quinoline-2- 1H), 8.25 (d, J = 8.5 Hz, 1H), m/z carboxamide7.90-7.82 (m, 2H), 7.71 (dd, J = 4.9, 2.3 Hz, 2H), 372.9 7.58 (d, J =3.5 Hz, 1H), 7.33 (d, J = 3.5 Hz, 1H), [M + H]⁺ 7.31-7.24 (m, 2H).Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS89 N-(pyridin-3- ppm 8.78-8.67 (m, 1H), 8.67-8.56 (m, 1H), (APCI)ylmethyl)quinoline-2- 8.48 (d, J = 8.6 Hz, 1H), 8.23 (d, J = 8.8 Hz, m/zcarboxamide 1H), 8.20-8.10 (m, 2H), 7.90-7.79 (m, 2H), 381.0 7.73-7.60(m, 3H), 7.32-7.21 (m, 2H), [M + H]⁺ 4.71 (s, 2H) Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 90N-[(3S)-2- ppm 8.49 (d, J = 8.6 Hz, 1H), 8.23 (d, J = 10.0 Hz, (APCI)oxotetrahydrofuran- 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.8 Hz,m/z 3-yl]quinoline-2- 2H), 7.73-7.61 (m, 2H), 7.27 (d, J = 8.8 Hz, 373.9carboxamide 2H), 4.84 (t, J = 10.0 Hz, 1H), 4.46 (dt, [M + H]⁺ J = 8.8,4.5 Hz, 1H), 4.34 (dt, J = 15.9, 7.9 Hz, 1H), 2.64-2.42 (m, 2H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 91N-[(2R)-1-hydroxy-3- ppm 8.48 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 9.0 Hz,(APCI) methylbutan-2- 1H), 8.16 (d, J = 8.5 Hz, 1H), m/z yl]quinoline-2-7.90-7.79 (m, 2H), 7.71-7.59 (m, 2H), 7.31-7.21 (m, 376.0 carboxamide2H), 3.92-3.79 (m, 1H), 3.64 (dd, J = 13.5, [M + H]⁺ 5.0 Hz, 2H),2.14-1.96 (m, 1H), 0.97 (m, 6H). Example 6-(4-cyanophenoxy)- ¹H NMR (400MHz, DMSO-d₆/D₂O, 90° C.) δ MS 92 N-(2- ppm 8.48 (d, J = 8.5 Hz, 1H),8.21 (d, J = 8.9 Hz, (APCI) thienylmethyl)quinoline- 1H), 8.16 (d, J =8.5 Hz, 1H), m/z 2-carboxamide 7.90-7.81 (m, 2H), 7.71-7.58 (m, 2H),7.34 (dd, J = 5.1, 385.9 1.2 Hz, 1H), 7.32-7.21 (m, 2H), 7.09 (d, J =3.4 Hz, [M + H]⁺ 1H), 7.03-6.92 (m, 1H), 4.76 (s, 2H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 93N-[2-(2- ppm 8.46 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 9.0 Hz, (APCI)thienyl)ethyl]quinoline- 1H), 8.14 (d, J = 8.5 Hz, 1H), m/z2-carboxamide 7.87-7.79 (m, 2H), 7.70-7.61 (m, 2H), 7.31-7.21 (m, 400.03H), 6.99-6.91 (m, 2H), 3.67 (t, J = 7.1 Hz, [M + H]⁺ 2H), 3.17 (t, J =7.1 Hz, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O,90° C.) δ MS 94 N-(2- ppm 8.47 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.9 Hz,(APCI) furylmethyl)quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), m/z2-carboxamide 7.89-7.81 (m, 2H), 7.69-7.60 (m, 2H), 7.54-7.49 (m, 369.91H), 7.29-7.22 (m, 2H), 6.41-6.37 (m, 1H), [M + H]⁺ 6.35-6.32 (m, 1H),4.60 (s, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O,90° C.) δ MS 95 N-(1-hydroxy-3- ppm 8.48 (d, J = 8.5 Hz, 1H), 8.22 (d, J= 9.0 Hz, (APCI) methylbutan-2- 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.84 (d,J = 8.9 Hz, m/z yl)quinoline-2- 2H), 7.70-7.61 (m, 2H), 7.26 (d, J = 8.8Hz, 376.0 carboxamide 2H), 3.90-3.79 (m, 1H), [M + H]⁺ 3.70-3.56 (m,2H), 2.10-1.96 (m, 1H), 1.04-0.93 (m, 6H). Example 6-(4-cyanophenoxy)-¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 96 N-[2-(pyrrolidin-1- ppm8.49 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 9.0 Hz, (APCI)yl)ethyl]quinoline-2- 1H), 8.16 (d, J = 8.5 Hz, 1H), m/z carboxamide7.89-7.81 (m, 2H), 7.71-7.64 (m, 2H), 7.30-7.23 (m, 387.0 2H), 3.77 (t,J = 6.1 Hz, 2H), 3.73-3.53 (m, [M + H]⁺ 2H), 3.44 (t, J = 6.1 Hz, 2H),3.22-3.00 (m, 2H), 2.13-1.85 (m, 4H). Example 6-(4-cyanophenoxy)- ¹H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 97 N-(pyridin-2- ppm 8.59 (d, J =4.9 Hz, 1H), 8.49 (d, J = 8.5 Hz, (APCI) ylmethyl)quinoline-2- 1H), 8.24(d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, m/z carboxamide 1H), 7.95 (dt,J = 7.7, 1.7 Hz, 1H), 381.0 7.89-7.79 (m, 2H), 7.71-7.62 (m, 2H), [M +H]⁺ 7.56 (d, J = 7.7 Hz, 1H), 7.49-7.41 (m, 1H), 7.31-7.21 (m, 2H), 4.77(s, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90°C.) δ MS 98 N-(pyridin-4- ppm 8.75-8.65 (m, 2H), 8.50 (d, J = 8.6 Hz,(APCI) ylmethyl)quinoline-2- 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.15 (d, J =8.5 Hz, m/z carboxamide 1H), 7.91-7.82 (m, 2H), 7.79 (d, J = 6.0 Hz,381.0 2H), 7.71-7.64 (m, 2H), 7.32-7.22 (m, [M + H]⁺ 2H), 4.78 (s, 2H).Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS99 N-[(5-methyl-2- ppm 8.47 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.9 Hz,(APCI) furyl)methyl]quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), m/z2-carboxamide 7.88-7.78 (m, 2H), 7.70-7.60 (m, 2H), 7.30-7.22 (m, 384.02H), 6.20 (d, J = 3.1 Hz, 1H), 6.03-5.95 (m, [M + H]⁺ 1H), 4.53 (s, 2H),2.24 (s, 3H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O,90° C.) δ MS 100 N-[3-(piperidin-1- ppm 8.48 (d, J = 8.6 Hz, 1H), 8.22(d, J = 8.7 Hz, (APCI) yl)propyl]quinoline- 1H), 8.15 (d, J = 8.5 Hz,1H), m/z 2-carboxamide 7.91-7.80 (m, 2H), 7.72-7.60 (m, 2H), 7.31-7.21(m, 415.1 2H), 3.55-3.39 (m, 4H), 3.20-3.08 (m, 2H), [M + H]⁺ 3.06-2.74(m, 2H), 2.12-1.95 (m, 2H), 1.94-1.55 (m, 6H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 101 N-(4-ppm 8.53 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 9.8 Hz, (APCI)phenoxyphenyl)quinoline- 1H), 8.24 (d, J = 8.5 Hz, 1H), m/z2-carboxamide 7.92-7.82 (m, 4H), 7.72-7.66 (m, 2H), 7.43-7.36 (m, 458.12H), 7.32-7.26 (m, 2H), 7.14 (t, J = 7.4 Hz, [M + H]⁺ 1H), 7.09-6.97 (m,4H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δMS 102 N-[3- ppm 8.48 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.9 Hz, (APCI)(trifluoromethoxy)benzyl]quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.84(d, J = 8.8 Hz, m/z 2- 2H), 7.69-7.62 (m, 2H), 464.0 carboxamide7.51-7.38 (m, 2H), 7.33 (s, 1H), 7.26 (d, J = 8.8 Hz, 2H), [M + H]⁺ 7.20(d, J = 7.8 Hz, 1H), 4.64 (s, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 103 N-(4- ppm 9.10-9.02 (m, 1H),8.47 (d, J = 8.6 Hz, (APCI) methylbenzyl)quinoline- 1H), 8.21 (d, J =9.0 Hz, 1H), 8.16 (d, J = 8.5 Hz, m/z 2-carboxamide 1H), 7.84 (d, J =8.8 Hz, 2H), 394.0 7.68-7.60 (m, 2H), 7.27 (t, J = 7.7 Hz, 4H), 7.14 (d,J = 7.9 Hz, [M + H]⁺ 2H), 4.55 (s, 2H), 2.28 (s, 3H). ExampleN-(1,3-benzodioxol- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 1045-ylmethyl)-6-(4- ppm 8.47 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 8.9 Hz,(APCI) cyanophenoxy)quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), m/z2-carboxamide 7.87-7.81 (m, 2H), 7.68-7.61 (m, 2H), 7.26 (d, J = 8.8 Hz,424.1 2H), 6.94 (s, 1H), 6.90-6.85 (m, 1H), [M + H]⁺ 6.83 (d, J = 7.9Hz, 1H), 5.94 (s, 2H), 4.50 (s, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 105 N-(2,3- ppm 8.95-8.87 (m, 1H),8.48 (d, J = 8.6 Hz, (APCI) dimethoxybenzyl)quinoline- 1H), 8.21 (d, J =9.0 Hz, 1H), 8.16 (d, J = 8.5 Hz, m/z 2-carboxamide 1H), 7.87-7.81 (m,2H), 7.69-7.61 (m, 440.1 2H), 7.30-7.22 (m, 2H), 7.06-6.90 (m, 3H), [M +H]⁺ 4.62 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H). Example 4-{[2-(azepan-1-¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 106 ylcarbonyl)quinolin- ppm8.40 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 9.1 Hz, (APCI)6-yl]oxy}benzonitrile 1H), 7.86-7.79 (m, 2H), 7.65 (d, J = 2.6 Hz, m/z1H), 7.63-7.56 (m, 2H), 7.27-7.20 (m, 372.0 2H), 3.71-3.61 (m, 2H),3.49-3.41 (m, 2H), [M + H]⁺ 1.85-1.73 (m, 2H), 1.69-1.58 (m, 6H).Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS107 N-(2-methoxyethyl)- ppm 8.39 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 9.1Hz, (APCI) N-propylquinoline-2- 1H), 7.87-7.80 (m, 2H), 7.67-7.57 (m,m/z carboxamide 3H), 7.29-7.20 (m, 2H), 3.71-3.07 (m, 9H), 390.01.78-1.46 (m, 2H), 1.05-0.55 (m, 3H). [M + H]⁺ Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 108 N-(2-ppm 8.47 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.8 Hz, (APCI)ethoxyethyl)quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.8Hz, m/z 2-carboxamide 2H), 7.69-7.62 (m, 2H), 7.26 (d, J = 8.8 Hz, 362.02H), 3.64-3.48 (m, 6H), 1.15 (t, J = 7.0 Hz, [M + H]⁺ 3H). Example N-(1-¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 109 benzylpyrrolidin-3- ppm8.48 (d, J = 8.6 Hz, 1H), 8.23 (d, J = 10.1 Hz, (APCI) yl)-6-(4- 1H),8.12 (d, J = 8.5 Hz, 1H), m/z cyanophenoxy)quinoline- 7.87-7.80 (m, 2H),7.69-7.63 (m, 2H), 7.58-7.44 (m, 449.1 2-carboxamide 4H), 7.29-7.23 (m,2H), 4.81-4.70 (m, 1H), [M + H]⁺ 4.45 (s, 2H), 3.74-3.56 (m, 2H),3.51-3.34 (m, 2H), 2.63-2.53 (m, 1H), 2.28-2.13 (m, 1H). Example4-[(2-{[3- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 110(trifluoromethyl)piperidin- ppm 8.43 (d, J = 8.5 Hz, 1H), 8.11 (d, J =9.0 Hz, (APCI) 1- 1H), 7.87-7.81 (m, 2H), 7.72-7.58 (m, m/zyl]carbonyl}quinolin- 3H), 7.28-7.22 (m, 2H), 4.78-3.49 (m, 2H), 426.16-yl)oxy]benzonitrile 3.22-2.95 (m, 2H), 2.76-2.54 (m, 1H), [M + H]⁺2.11-1.97 (m, 1H), 1.97-1.47 (m, 3H). Example 4-{[2-(2,3-dihydro- ¹H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 111 1H-indol-1- ppm 8.48 (d, J = 8.5Hz, 1H), 8.17 (d, J = 9.0 Hz, (APCI) ylcarbonyl)quinolin- 1H), 7.85 (d,J = 8.8 Hz, 3H), 7.69 (d, J = 2.6 Hz, m/z 6-yl]oxy}benzonitrile 1H),7.64 (dd, J = 9.1, 2.8 Hz, 1H), 392.0 7.31 (d, J = 7.5 Hz, 1H), 7.27 (d,J = 8.8 Hz, [M + H]⁺ 2H), 7.19 (s, 1H), 7.13-7.05 (m, 1H), 4.31 (t, J =8.3 Hz, 2H), 3.16 (t, J = 8.3 Hz, 3H). Example 4-{[2-(piperazin-1- ¹HNMR (300 MHz, DMSO-d₆) δ ppm 8.45 (d, MS 112 ylcarbonyl)quinolin- J =8.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), (ESI) 6-yl]oxy}benzonitrile7.94-7.87 (m, 2H), 7.73 (d, J = 2.6 Hz, 1H), m/z 7.69-7.62 (m, 2H),7.30-7.22 (m, 2H), 359.4 3.66-3.57 (m, 2H), 3.36-3.32 (m, 2H), [M + H]⁺2.83-2.75 (m, 2H), 2.71-2.62 (m, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR(501 MHz, DMSO-d₆) δ ppm 9.46 (d, MS 113 N-[(3R)-2- J = 8.5 Hz, 1H),8.53 (d, J = 8.6 Hz, 1H), (ESI) oxotetrahydrofuran- 8.22 (d, J = 9.0 Hz,1H), 8.15 (d, J = 8.5 Hz, 1H), m/z 3-yl]quinoline-2- 7.94-7.90 (m, 2H),7.76-7.70 (m, 2H), 374.1 carboxamide 7.33-7.28 (m, 2H), 4.91 (dd, J =18.7, 10.0 Hz, [M + H]⁺ 1H), 4.48-4.40 (m, 1H), 4.35-4.27 (m, 1H),2.53-2.46 (m, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.86 (d, MS 114 N-(tetrahydrofuran-3- J = 7.3 Hz, 1H), 8.51 (d, J= 8.5 Hz, 1H), (ESI) yl)quinoline-2- 8.24 (d, J = 9.1 Hz, 1H), 8.13 (d,J = 8.5 Hz, 1H), m/z carboxamide 7.95-7.89 (m, 2H), 7.75-7.67 (m, 2H),360.1 7.33-7.26 (m, 2H), 4.61-4.49 (m, 1H), [M + H]⁺ 3.96-3.83 (m, 2H),3.79-3.64 (m, 2H), 2.30-2.15 (m, 1H), 2.11-2.00 (m, 1H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 115 N- 11.92 (s,1H), 8.46 (d, J = 8.6 Hz, 1H), 8.24 (d, J = 8.9 Hz, (ESI)(methylsulfonyl)quinoline- 1H), 8.11 (d, J = 8.5 Hz, 1H), m/z2-carboxamide 7.95-7.88 (m, 2H), 7.74-7.65 (m, 2H), 368.0 7.33-7.26 (m,2H), 3.21 (s, 3H). [M + H]⁺ Example 6-(4-cyanophenoxy)- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.65 (d, MS 116 N-(tetrahydro-2H- J = 8.5 Hz, 1H), 8.51(d, J = 8.5 Hz, 1H), (ESI) pyran-3-yl)quinoline- 8.24 (d, J = 9.1 Hz,1H), 8.15 (d, J = 8.5 Hz, 1H), m/z 2-carboxamide 7.98-7.86 (m, 2H),7.78-7.64 (m, 2H), 374.1 7.36-7.23 (m, 2H), 4.10-3.92 (m, 1H), 3.80 (dd,[M + H]⁺ J = 10.8, 3.0 Hz, 1H), 3.76-3.69 (m, 1H), 3.50-3.37 (m, 2H),2.03-1.87 (m, 1H), 1.86-1.67 (m, 2H), 1.67-1.50 (m, 1H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.85 (d, MS 117N-[(3R)- J = 7.3 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), (ESI)tetrahydrofuran-3- 8.24 (d, J = 9.1 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H),m/z yl]quinoline-2- 7.98-7.86 (m, 2H), 7.78-7.64 (m, 2H), 360.1carboxamide 7.35-7.23 (m, 2H), 4.63-4.47 (m, 1H), [M + H]⁺ 3.96-3.85 (m,2H), 3.75 (td, J = 8.2, 6.1 Hz, 1H), 3.69 (dd, J = 8.9, 4.5 Hz, 1H),2.31-2.14 (m, 1H), 2.10-2.00 (m, 1H). Example 6-(4-cyanophenoxy)- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.85 (d, MS 118 N-[(3S)- J = 7.3 Hz, 1H), 8.51(d, J = 8.5 Hz, 1H), (ESI) tetrahydrofuran-3- 8.24 (d, J = 9.1 Hz, 1H),8.13 (d, J = 8.5 Hz, 1H), m/z yl]quinoline-2- 7.98-7.86 (m, 2H),7.78-7.64 (m, 2H), 360.1 carboxamide 7.35-7.23 (m, 2H), 4.63-4.47 (m,1H), [M + H]⁺ 3.96-3.85 (m, 2H), 3.75 (td, J = 8.2, 6.1 Hz, 1H), 3.69(dd, J = 8.9, 4.5 Hz, 1H), 2.31-2.14 (m, 1H), 2.10-2.00 (m, 1H). Example6-(4-cyanophenoxy)- 1H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 119N-[(1R,2S)-2- 8.55-8.49 (m, 2H), 8.24 (d, J = 9.1 Hz, 1H), (APCI)hydroxycyclohexyl]quinoline- 8.18 (d, J = 8.5 Hz, 1H), 7.94-7.88 (m,2H), m/z 2- 7.76-7.66 (m, 2H), 7.33-7.25 (m, 2H), 388.0 carboxamide3.97-3.85 (m, 2H), 1.82-1.50 (m, 6H), [M + H]⁺ 1.42-1.31 (m, 2H).Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 120N-[(1S,2S)-2- 8.62 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 8.6 Hz, (APCI)hydroxycyclohexyl]quinoline- 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.16 (d, J =8.6 Hz, m/z 2- 1H), 7.93-7.88 (m, 2H), 7.75-7.66 (m, 388.0 carboxamide2H), 7.32-7.25 (m, 2H), 3.72-3.61 (m, 1H), [M + H]⁺ 3.58-3.48 (m, 1H),2.01-1.90 (m, 2H), 1.72-1.60 (m, 2H), 1.43-1.33 (m, 1H), 1.33-1.20 (m,3H). Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS121 N-[(1S,2S)-2- 8.51 (d, J = 8.6 Hz, 1H), 8.27 (d, J = 9.0 Hz, (APCI)hydroxycyclopentyl]quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.91 (d, J= 8.8 Hz, m/z 2- 2H), 7.75-7.66 (m, 2H), 7.29 (d, J = 8.8 Hz, 374.0carboxamide 2H), 4.16-4.01 (m, 2H), 2.12-2.02 (m, [M + H]⁺ 1H),1.97-1.89 (m, 1H), 1.76-1.67 (m, 2H), 1.64-1.48 (m, 2H). Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 122N-(2-hydroxy-2- 8.54 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 9.1 Hz, (APCI)methylpropyl)quinoline- 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.94-7.87 (m, m/z2-carboxamide 2H), 7.74 (d, J = 2.7 Hz, 1H), 7.71 (dd, J = 9.1, 362.02.7 Hz, 1H), 7.32-7.26 (m, 2H), 3.38 (s, 2H), [M + H]⁺ 1.17 (s, 6H).Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 123N-[1- 8.51 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 8.9 Hz, (APCI)(hydroxymethyl)cyclopropyl]quinoline- 1H), 8.14 (d, J = 8.5 Hz, 1H),7.95-7.87 (m, m/z 2- 2H), 7.74-7.66 (m, 2H), 7.32-7.24 (m, 2H), 360.0carboxamide 3.57 (s, 2H), 0.85 (s, 4H). [M + H]⁺ Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 124N-(1-hydroxy-2- 8.52 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 9.0 Hz, (APCI)methylpropan-2- 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.95-7.88 (m, m/zyl)quinoline-2- 2H), 7.73-7.67 (m, 2H), 7.32-7.25 (m, 2H), 362.0carboxamide 3.54 (s, 2H), 1.41 (s, 6H). [M + H]⁺ Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 125N-(trans-4- 8.50 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 9.0 Hz, (APCI)hydroxycyclohexyl)quinoline- 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.95-7.86(m, m/z 2- 2H), 7.75-7.62 (m, 2H), 7.28 (d, J = 8.8 Hz, 388.0carboxamide 2H), 3.84-3.77 (m, 1H), 3.52-3.40 (m, 1H), [M + H]⁺1.95-1.80 (m, 4H), 1.59-1.44 (m, 2H), 1.37-1.22 (m, 2H). Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 126 N-(1,3-8.53 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 9.1 Hz, (APCI) dihydroxypropan-2-1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94-7.88 (m, m/z yl)quinoline-2- 2H),7.76-7.67 (m, 2H), 7.32-7.26 (m, 2H), 364.0 carboxamide 4.08-3.99 (m,1H), 3.69-3.55 (m, 4H). [M + H]⁺ Example 6-(4-cyanophenoxy)- ¹H NMR (500MHz, DMSO-d₆/D₂O) δ ppm MS 127 N-(1-hydroxypropan- 8.52 (d, J = 8.6 Hz,1H), 8.26 (d, J = 9.0 Hz, (APCI) 2-yl)quinoline-2- 1H), 8.16 (d, J = 8.5Hz, 1H), 7.94-7.87 (m, m/z carboxamide 2H), 7.75-7.66 (m, 2H), 7.33-7.25(m, 2H), 348.0 4.17-4.04 (m, 1H), 3.60-3.46 (m, 2H), [M + H]⁺ 1.23 (d, J= 6.7 Hz, 3H). Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O)δ ppm MS 128 N-(2- 8.52 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 9.1 Hz, (APCI)hydroxypropyl)quinoline- 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.94-7.88 (m,m/z 2-carboxamide 2H), 7.72 (dd, J = 11.8, 5.8 Hz, 2H), 348.0 7.33-7.26(m, 2H), 3.91-3.83 (m, 1H), 3.43 (dd, J = 13.2, [M + H]⁺ 4.8 Hz, 1H),3.29 (dd, J = 13.2, 7.0 Hz, 1H), 1.12 (d, J = 6.2 Hz, 3H). Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 129N-[(1S,3R)-3- 8.51 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 9.0 Hz, (APCI)hydroxycyclohexyl]quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.91 (d, J =8.8 Hz, m/z 2- 2H), 7.74-7.67 (m, 2H), 7.28 (d, J = 8.8 Hz, 388.0carboxamide 2H), 4.00-3.84 (m, 1H), 3.65-3.51 (m, [M + H]⁺ 1H),2.08-1.97 (m, 1H), 1.85-1.71 (m, 3H), 1.52-1.36 (m, 2H), 1.36-1.25 (m,1H), 1.25-1.14 (m, 1H) Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz,DMSO-d₆/D₂O) δ ppm MS 130 N-[(1S,3R)-3- 8.51 (d, J = 8.5 Hz, 1H), 8.21(d, J = 9.1 Hz, (APCI) hydroxycyclopentyl]quinoline- 1H), 8.15 (d, J =8.5 Hz, 1H), 7.93-7.88 (m, m/z 2- 2H), 7.75-7.66 (m, 2H), 7.32-7.24 (m,2H), 374.0 carboxamide 4.45-4.38 (m, 1H), 4.28-4.21 (m, 1H), [M + H]⁺2.15-2.07 (m, 1H), 2.06-1.94 (m, 1H), 1.84-1.69 (m, 3H), 1.68-1.61 (m,1H). Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS131 N-[(1R,2S)-2- 8.52 (d, J = 7.3 Hz, 1H), 8.23 (d, J = 9.1 Hz, (APCI)hydroxycyclopentyl]quinoline- 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94-7.88(m, m/z 2- 2H), 7.75-7.67 (m, 2H), 7.32-7.26 (m, 2H), 374.0 carboxamide4.14-4.08 (m, 2H), 2.06-1.96 (m, 1H), [M + H]⁺ 1.95-1.76 (m, 2H),1.72-1.51 (m, 3H). Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz,DMSO-d₆/D₂O) δ ppm MS 132 N-[(1S,3S)-3- 8.51 (d, J = 8.6 Hz, 1H), 8.27(d, J = 9.1 Hz, (APCI) hydroxycyclohexyl]quinoline- 1H), 8.15 (d, J =8.5 Hz, 1H), 7.94-7.88 (m, m/z 2- 2H), 7.75-7.66 (m, 2H), 7.33-7.22 (m,2H), 388.0 carboxamide 4.32-4.21 (m, 1H), 4.01 (s, 1H), [M + H]⁺1.87-1.77 (m, 2H), 1.77-1.68 (m, 2H), 1.63-1.36 (m, 4H) Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 133 N-(cis-4-8.51 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 9.0 Hz, (APCI)hydroxycyclohexyl)quinoline- 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.94-7.88(m, m/z 2- 2H), 7.74-7.68 (m, 2H), 7.31-7.26 (m, 2H), 388.0 carboxamide3.89 (t, J = 9.4 Hz, 1H), 3.81-3.76 (m, 1H), [M + H]⁺ 1.89-1.77 (m, 2H),1.73-1.53 (m, 6H). Example 6-(4-cyanophenoxy)- ¹H NMR (500 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 134 N-(3-hydroxybutan- ppm 8.52 (d, J = 8.5Hz, 1H), 8.26 (d, J = 9.1 Hz, (APCI) 2-yl)quinoline-2- 1H), 8.17 (d, J =8.5 Hz, 1H), m/z carboxamide 7.94-7.88 (m, 2H), 7.74-7.68 (m, 2H),7.32-7.24 (m, 362.0 2H), 4.01-3.88 (m, 1H), 3.82-3.76 (m, 1H), [M + H]⁺1.19 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H). Example6-(4-cyanophenoxy)- ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ ppm MS 135N-(2-hydroxy-3- 8.53 (d, J = 8.6 Hz, 1H), 8.24 (d, J = 9.1 Hz, (APCI)methylbutyl)quinoline- 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 9.1,m/z 2-carboxamide 2.3 Hz, 2H), 7.79-7.66 (m, 2H), 376.0 7.34-7.24 (m,2H), 3.57 (dd, J = 13.4, 3.9 Hz, 1H), [M + H]⁺ 3.50-3.41 (m, 1H), 3.26(dd, J = 13.4, 7.9 Hz, 1H), 1.77-1.57 (m, 1H), 0.99-0.85 (m, 6H).Example 6-(4-cyanophenoxy)- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.28 (d, MS136 N-(1,1- J = 8.2 Hz, 1H), 8.52 (d, J = 8.3 Hz, 1H), (ESI)dioxidotetrahydrothiophen- 8.23 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 8.5Hz, 1H), m/z 3-yl)quinoline- 8.00-7.84 (m, 2H), 7.80-7.64 (m, 2H), 408.12-carboxamide 7.38-7.22 (m, 2H), 4.90-4.71 (m, 1H), [M + H]⁺ 3.55-3.15(m, 4H), 2.48-2.25 (m, 2H). Example 4-({2-[(3- ¹H NMR (300 MHz, DMSO-d₆)δ ppm 8.48 (d, MS 137 oxopiperazin-1- J = 8.5 Hz, 1H), 8.22-8.07 (m,2H), (ESI) yl)carbonyl]quinolin- 7.99-7.82 (m, 2H), 7.79-7.73 (m, 2H),7.68 (dd, J = 9.1, m/z 6-yl}oxy)benzonitrile 2.7 Hz, 1H), 7.36-7.19 (m,2H), 373.1 4.26-4.12 (m, 2H), 3.95-3.81 (m, 1H), [M + H]⁺ 3.81-3.66 (m,1H), 3.36-3.26 (m, 2H). Example 4-[(2-{[4-(morpholin- ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.45 (d, MS 138 4-yl)piperidin-1- J = 8.4 Hz, 1H), 8.12(d, J = 9.1 Hz, 1H), (ESI) yl]carbonyl}quinolin- 7.94-7.86 (m, 2H), 7.73(d, J = 2.7 Hz, 1H), m/z 6-yl)oxy]benzonitrile 7.70-7.62 (m, 2H),7.31-7.22 (m, 2H), 4.52 (d, J = 12.3 Hz, 443.1 1H), 3.73 (d, J = 13.8Hz, 1H), [M + H]⁺ 3.61-3.51 (m, 4H), 3.15-3.01 (m, 1H), 2.98-2.83 (m,1H), 2.49-2.41 (m, 5H), 1.92 (d, J = 12.3 Hz, 1H), 1.73 (d, J = 12.0 Hz,1H), 1.43 (qd, J = 11.9, 4.0 Hz, 2H). Example 6-(4-cyanophenoxy)- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 9.26 (d, MS 139 N-[(4R)-6-fluoro-3,4- J = 8.8Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), (ESI) dihydro-2H-chromen- 8.21 (dd, J= 8.8, 3.4 Hz, 2H), 8.00-7.84 (m, 2H), m/z 4-yl]quinoline-2- 7.75 (d, J= 2.7 Hz, 1H), 7.69 (dd, J = 9.1, 2.7 Hz, 440.0 carboxamide 1H),7.32-7.25 (m, 2H), 7.07-6.94 (m, [M + H]⁺ 2H), 6.84 (dd, J = 8.9, 4.9Hz, 1H), 5.45-5.27 (m, 1H), 4.44-4.16 (m, 2H), 2.33-2.07 (m, 2H).Example 4-({2-[(4-tert- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.45 (d, MS 140butylpiperazin-1- J = 8.4 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), (ESI)yl)carbonyl]quinolin- 7.93-7.87 (m, 2H), 7.73 (d, J = 2.7 Hz, 1H), m/z6-yl}oxy)benzonitrile 7.71-7.62 (m, 2H), 7.30-7.22 (m, 2H), 415.03.71-3.62 (m, 2H), 3.45-3.37 (m, 2H), [M + H]⁺ 2.65-2.55 (m, 2H),2.48-2.45 (m, 2H), 1.02 (s, 9H). Example 6-(4-cyanophenoxy)- ¹H NMR (300MHz, DMSO-d₆) δ ppm 9.26 (d, MS 141 N-[(4R)-6-fluoro-2,2- J = 9.0 Hz,1H), 8.55 (d, J = 8.4 Hz, 1H), (ESI) dimethyl-3,4- 8.21 (t, J = 9.1 Hz,2H), 7.96-7.86 (m, 2H), m/z dihydro-2H-chromen- 7.79-7.64 (m, 2H),7.33-7.25 (m, 2H), 7.00 (td, J = 8.5, 467.9 4-yl]quinoline-2- 3.1 Hz,1H), 6.93 (dd, J = 9.4, 3.1 Hz, [M + H]⁺ carboxamide 1H), 6.80 (dd, J =8.9, 4.9 Hz, 1H), 5.44-5.30 (m, 1H), 2.26-2.14 (m, 1H), 2.09 (dd, J =13.1, 6.7 Hz, 1H), 1.43 (s, 3H), 1.32 (s, 3H). Example 4-[(2-{[(3S)-3-¹H NMR (300 MHz, DMSO-d₆, rotamers) δ MS 142 isopropylpiperazin-1- ppm8.45 (d, J = 8.5 Hz, 1H), 8.11 (dd, J = 9.1, (ESI) yl]carbonyl}quinolin-3.3 Hz, 1H), 7.99-7.82 (m, 2H), m/z 6-yl)oxy]benzonitrile 7.79-7.58 (m,3H), 7.36-7.18 (m, 2H), 4.41 (dd, J = 25.9, 401.1 12.3 Hz, 1H), 3.81 (d,J = 12.3 Hz, [M + H]⁺ 0.5H), 3.55 (d, J = 13.2 Hz, 0.5H), 3.16-2.95 (m,1H), 2.89-2.54 (m, 3H), 2.47-2.19 (m, 2H), 1.71-1.56 (m, 0.5H),1.55-1.40 (m, 0.5H), 0.96 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz,1.5H), 0.70 (d, J = 6.8 Hz, 1.5H). Example 6-(4-cyanophenoxy)- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 9.15 (d, MS 143 N-(1-methyl-2- J = 8.4 Hz, 1H),8.53 (d, J = 8.4 Hz, 1H), (ESI) oxopyrrolidin-3- 8.21 (d, J = 9.0 Hz,1H), 8.15 (d, J = 8.5 Hz, 1H), m/z yl)quinoline-2- 8.00-7.84 (m, 2H),7.81-7.64 (m, 2H), 387.1 carboxamide 7.39-7.23 (m, 2H), 4.64 (q, J = 9.1Hz, 1H), [M + H]⁺ 3.41-3.33 (m, 2H), 2.80 (s, 3H), 2.45-2.30 (m, 1H),2.18-2.03 (m, 1H). Example 6-(4-cyanophenoxy)- ¹H NMR (300 MHz, DMSO-d₆)δ ppm 9.51 (t, MS 144 N-(1,3-oxazol-2- J = 6.1 Hz, 1H), 8.53 (d, J = 8.7Hz, 1H), (ESI) ylmethyl)quinoline-2- 8.22 (d, J = 9.0 Hz, 1H), 8.16 (d,J = 8.5 Hz, 1H), m/z carboxamide 8.05 (d, J = 0.7 Hz, 1H), 8.00-7.84 (m,2H), 371.0 7.82-7.65 (m, 2H), 7.39-7.23 (m, 2H), [M + H]⁺ 7.17 (d, J =0.7 Hz, 1H), 4.68 (d, J = 6.1 Hz, 2H). Example 6-(4-cyanophenoxy)- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.05 (t, MS 145 N-[2-(methylamino)- J = 5.9Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), (ESI) 2-oxoethyl]quinoline- 8.22 (d,J = 9.1 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), m/z 2-carboxamide 7.98-7.86(m, 3H), 7.80-7.66 (m, 2H), 360.9 7.36-7.24 (m, 2H), 3.97 (d, J = 5.9Hz, 2H), [M + H]⁺ 2.62 (d, J = 4.6 Hz, 3H). Example N-(2-amino-2- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.95 (t, MS 146 oxoethyl)-6-(4- J = 5.8 Hz,1H), 8.53 (d, J = 8.5 Hz, 1H), (ESI) cyanophenoxy)quinoline- 8.22 (d, J= 9.1 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), m/z 2-carboxamide 8.00-7.84 (m,2H), 7.81-7.64 (m, 2H), 347.0 7.48 (s, 1H), 7.38-7.22 (m, 2H), 7.13 (s,1H), [M + H]⁺ 3.96 (d, J = 5.8 Hz, 2H). Example 6-(4-cyanophenoxy)- ¹HNMR (300 MHz, DMSO-d₆) δ ppm 9.15 (t, MS 147 N-(2- J = 6.1 Hz, 1H), 8.52(d, J = 8.5 Hz, 1H), (ESI) sulfamoylethyl)quinoline- 8.25-8.09 (m, 2H),8.00-7.84 (m, 2H), m/z 2-carboxamide 7.81-7.63 (m, 2H), 7.38-7.22 (m,2H), 7.00 (s, 397.1 2H), 3.79 (dd, J = 13.7, 6.3 Hz, 2H), [M + H]⁺3.35-3.27 (m, 2H). Example 4-({2-[(1,1- ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.50 (d, MS 148 dioxidothiomorpholin- J = 8.4 Hz, 1H), 8.16 (d, J = 9.0Hz, 1H), (ESI) 4- 7.94-7.87 (m, 2H), 7.82 (d, J = 8.5 Hz, 1H), m/zyl)carbonyl]quinolin- 7.74 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.1, 2.7Hz, 408.1 6-yl}oxy)benzonitrile 1H), 7.31-7.22 (m, 2H), 4.15-4.07 (m,2H), [M + H]⁺ 3.96-3.88 (m, 2H), 3.39-3.27 (m, 4H). ExampleN-(tetrahydrofuran-3- ¹H NMR (300 MHz, DMSO-d₆) δ ppm MS 149 yl)-6-{[5-8.86 (d, J = 7.3 Hz, 1H), 8.65-8.57 (m, 1H), (ESI⁺)(trifluoromethyl)pyridin- 8.53 (d, J = 8.4 Hz, 1H), 8.31 (dd, J = 8.7,2.5 Hz, m/z 404 2- 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 8.5 Hz,(M + H)⁺ yl]oxy}quinoline-2- 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.76 (dd, J= 9.2, carboxamide 2.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 4.63-4.48 (m,1H), 3.99-3.85 (m, 2H), 3.77 (dt, J = 8.2, 4.1 Hz, 1H), 3.70 (dd, J =8.8, 4.5 Hz, 1H), 2.31-2.16 (m, 1H), 2.13-1.96 (m, 1H). ExampleN-(2-amino-2- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.96 (t, MS 150oxoethyl)-6-{[5- J = 5.7 Hz, 1H), 8.65-8.60 (m, 1H), 8.55 (d, J = 8.5Hz, (ESI⁺) (trifluoromethyl)pyridin- 1H), 8.31 (dd, J = 8.5, 2.7 Hz,1H), m/z 391 2- 8.21 (d, J = 6.7 Hz, 1H), 8.18 (d, J = 6.1 Hz, (M + H)⁺,yl]oxy}quinoline-2- 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.77 (dd, J = 9.1,389 carboxamide 2.7 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.7 Hz, (M − H)⁺1H), 7.14 (s, 1H), 3.97 (d, J = 5.8 Hz, 2H) Example N-(pyridin-2- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 9.52 (t, MS 151 ylmethyl)-6-{[5- J = 6.1 Hz,1H), 8.65-8.51 (m, 3H), (ESI⁺) (trifluoromethyl)pyridin- 8.36-8.27 (m,1H), 8.21 (dd, J = 8.8, 4.6 Hz, 2H), m/z 425 2- 7.95 (d, J = 2.6 Hz,1H), 7.83-7.71 (m, 2H), (M + H)⁺ yl]oxy}quinoline-2- 7.46-7.35 (m, 2H),7.33-7.23 (m, 1H), carboxamide 4.70 (d, J = 6.1 Hz, 2H) Examplepiperazin-1-yl(6-{[4- ¹H NMR (300 MHz, DMSO-d₆) δ ppm MS 152(trifluoromethyl)pyridin- 8.46 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 5.3 Hz,1H), (ESI⁺) 2- 8.10 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 2.6 Hz, m/z 403yl]oxy}quinolin-2- 1H), 7.73-7.64 (m, 2H), 7.62 (s, 1H), (m + H)⁺yl)methanone 7.58-7.52 (m, 1H), 3.68-3.58 (m, 2H), 3.39-3.32 (m, 2H),2.84-2.76 (m, 2H), 2.71-2.64 (m, 2H) Example piperazin-1-yl(6-{[6- ¹HNMR (300 MHz, DMSO-d₆) δ ppm MS 153 (trifluoromethyl)pyridin- 8.46 (d, J= 8.3 Hz, 1H), 8.23-8.14 (m, 1H), (ESI⁺) 2- 8.10 (d, J = 9.1 Hz, 1H),7.86 (d, J = 2.6 Hz, 1H), m/z 403 yl]oxy}quinolin-2- 7.74-7.64 (m, 3H),7.48 (d, J = 8.3 Hz, 1H), (M + H)⁺ yl)methanone 3.68-3.58 (m, 2H),3.39-3.33 (m, 2H), 2.84-2.75 (m, 2H), 2.71-2.63 (m, 2H), 2.45 (s, 1H)Example 6-{[3-chloro-5- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.30 (d, MS 154(trifluoromethyl)pyridin- J = 8.1 Hz, 1H), 8.67-8.63 (m, 1H), (ESI)2-yl]oxy}-N-(1,1- 8.59-8.51 (m, 2H), 8.23 (d, J = 9.2 Hz, 1H), 8.19 (d,m/z dioxidotetrahydrothiophen- J = 8.5 Hz, 1H), 7.99 (d, J = 2.6 Hz,1H), 486.1 3-yl)quinoline- 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 4.90-4.73 (m,1H), [M + H]⁺ 2-carboxamide 3.56-3.33 (m, 3H), 3.26-3.17 (m, 1H),2.47-2.24 (m, 2H). Example N-(1,1- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.31(d, MS 155 dioxidotetrahydrothiophen- J = 8.2 Hz, 1H), 9.19-9.15 (m,2H), 8.56 (d, J = 8.5 Hz, (ESI) 3-yl)-6-{[5- 1H), 8.23 (d, J = 9.2 Hz,1H), m/z (trifluoromethyl)pyrimidin- 8.19 (d, J = 8.5 Hz, 1H), 8.03 (d,J = 2.6 Hz, 1H), 453.1 2- 7.85 (dd, J = 9.2, 2.7 Hz, 1H), 4.91-4.72 (m,[M + H]⁺ yl]oxy}quinoline-2- 1H), 3.57-3.33 (m, 3H), 3.27-3.15 (m, 1H),carboxamide 2.46-2.23 (m, 2H). Example 2-oxa-6- ¹H NMR (300 MHz,DMSO-d₆) δ ppm MS 156 azaspiro[3.3]hept-6- 8.62-8.58 (m, 1H), 8.48 (d, J= 8.6 Hz, 1H), (ESI) yl(6-{[5- 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.17 (d,J = 9.1 Hz, m/z (trifluoromethyl)pyridin- 1H), 8.04 (d, J = 8.6 Hz, 1H),7.89 (d, J = 2.6 Hz, 416.1 2- 1H), 7.74 (dd, J = 9.1, 2.7 Hz, 1H), [M +H]⁺ yl]oxy}quinolin-2- 7.40 (d, J = 8.8 Hz, 1H), 4.93 (s, 2H), 4.74 (s,4H), yl)methanone 4.31 (s, 2H). Example 2,6- ¹H NMR (300 MHz, DMSO-d₆) δppm MS 157 diazaspiro[3.3]hept- 8.62-8.57 (m, 1H), 8.47 (d, J = 8.4 Hz,1H), (ESI) 2-yl(6-{[5- 8.30 (dd, J = 8.8, 2.7 Hz, 1H), 8.17 (d, J = 9.1Hz, m/z (trifluoromethyl)pyridin- 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.89(d, J = 2.6 Hz, 415.2 2- 1H), 7.73 (dd, J = 9.1, 2.7 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.40 (d, J = 8.6 Hz, 1H), 4.82 (s, 2H), 4.20 (s, 2H),yl)methanone 3.62 (s, 4H). Example 6-[(5-cyanopyridin-2- ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.32 (d, MS 158 yl)oxy]-N-(1,1- J = 8.1 Hz, 1H),8.68 (d, J = 2.2 Hz, 1H), (ESI) dioxidotetrahydrothiophen- 8.55 (d, J =8.5 Hz, 1H), 8.39 (dd, J = 8.7, 2.3 Hz, m/z 3-yl)quinoline- 1H), 8.22(d, J = 9.1 Hz, 1H), 8.18 (d, J = 8.5 Hz, 409.1 2-carboxamide 1H), 7.93(d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1, [M + H]⁺ 2.6 Hz, 1H), 7.40 (d, J= 8.7 Hz, 1H), 4.87-4.75 (m, 1H), 3.51 (dd, J = 13.1, 7.7 Hz, 1H),3.44-3.40 (m, 1H), 3.33-3.30 (m, 1H), 3.30-3.17 (m, 1H), 2.49-2.44 (m,1H), 2.42-2.31 (m, 1H). Example 6-(4-cyanophenoxy)- ¹H NMR (300 MHz,DMSO-d₆) δ ppm 9.28 (d, MS 159 N-[(3S)-1,1- J = 8.2 Hz, 1H), 8.52 (d, J= 8.5 Hz, 1H), (ESI) dioxidotetrahydrothiophen- 8.23 (d, J = 8.8 Hz,1H), 8.15 (d, J = 8.5 Hz, 1H), m/z 3-yl]quinoline- 7.96-7.87 (m, 2H),7.78-7.68 (m, 2H), 408.2 2-carboxamide 7.35-7.27 (m, 2H), 4.89-4.72 (m,1H), [M + H]⁺ 3.56-3.46 (m, 1H), 3.46-3.35 (m, 1H), 3.28-3.14 (m, 2H),2.48-2.41 (m, 1H), 2.41-2.24 (m, 1H). Example 6-(4-cyanophenoxy)- ¹H NMR(300 MHz, DMSO-d₆) δ ppm 9.28 (d, MS 160 N-[(3R)-1,1- J = 8.2 Hz, 1H),8.52 (d, J = 8.5 Hz, 1H), (ESI) dioxidotetrahydrothiophen- 8.23 (d, J =8.8 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), m/z 3-yl]quinoline- 7.96-7.87 (m,2H), 7.78-7.68 (m, 2H), 408.2 2-carboxamide 7.35-7.27 (m, 2H), 4.89-4.72(m, 1H), [M + H]⁺ 3.56-3.46 (m, 1H), 3.46-3.35 (m, 1H), 3.28-3.14 (m,2H), 2.48-2.41 (m, 1H), 2.41-2.24 (m, 1H). Example N-(1,1- ¹H NMR (300MHz, DMSO-d₆) δ ppm 9.29 (d, MS 161 dioxidotetrahydrothiophen- J = 8.2Hz, 1H), 8.58-8.48 (m, 3H), 8.18 (t, J = 8.4 Hz, (ESI) 3-yl)-6-[(5- 2H),7.89 (d, J = 2.6 Hz, 1H), m/z methylpyrimidin-2- 7.74 (dd, J = 9.2, 2.7Hz, 1H), 4.88-4.73 (m, 1H), 399.2 yl)oxy]quinoline-2- 3.51 (dd, J =13.2, 7.7 Hz, 1H), 3.47-3.35 (m, [M + H]⁺ carboxamide 2H), 3.27-3.16 (m,1H), 2.48-2.29 (m, 2H), 2.25 (s, 3H). Example 6-[(4,6- ¹H NMR (300 MHz,DMSO-d₆) δ ppm 9.28 (d, MS 162 dimethylpyrimidin-2- J = 8.2 Hz, 1H),8.54 (d, J = 8.5 Hz, 1H), (ESI) yl)oxy]-N-(1,1- 8.17 (dd, J = 8.8, 6.0Hz, 2H), 7.88 (d, J = 2.6 Hz, m/z dioxidotetrahydrothiophen- 1H), 7.73(dd, J = 9.2, 2.6 Hz, 1H), 7.09 (s, 413.1 3-yl)quinoline- 1H), 4.89-4.72(m, 1H), 3.51 (dd, J = 13.1, [M + H]⁺ 2-carboxamide 7.7 Hz, 1H),3.47-3.34 (m, 2H), 3.27-3.18 (m, 1H), 2.48-2.37 (m, 2H), 2.35 (s, 6H).Example N-(1,1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (d, MS 163dioxidotetrahydrothiophen- J = 8.2 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H),(ESI) 3-yl)-6-[(4- 8.49 (d, J = 5.0 Hz, 1H), 8.18 (dd, J = 12.3, 8.8 Hz,m/z methylpyrimidin-2- 2H), 7.90 (d, J = 2.6 Hz, 1H), 7.75 (dd, J = 9.1,399.1 yl)oxy]quinoline-2- 2.6 Hz, 1H), 7.21 (d, J = 5.0 Hz, 1H), [M +H]⁺ carboxamide 4.88-4.74 (m, 1H), 3.51 (dd, J = 13.2, 7.7 Hz, 1H),3.45-3.39 (m, 1H), 3.32-3.17 (m, 2H), 2.49-2.44 (m, 1H), 2.42 (s, 3H),2.40-2.31 (m, 1H). Example (3aR,6aS)- ¹H NMR (300 MHz, DMSO-d₆,rotamers) δ MS 164 hexahydropyrrolo[3,4- ppm 8.62-8.56 (m, 1H), 8.46 (d,J = 8.4 Hz, (ESI) c]pyrrol-2(1H)-yl(6- 1H), 8.33-8.26 (m, 1H), 8.14 (t,J = 9.1 Hz, m/z {[5- 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.81 (t, J = 8.7 Hz,429.2 (trifluoromethyl)pyridin- 1H), 7.74-7.65 (m, 1H), 7.39 (d, J = 8.8Hz, [M + H]⁺ 2- 1H), 4.16-3.71 (m, 2.5H), yl]oxy}quinolin-2- 3.57-3.38(m, 2.5H), 3.15-3.07 (m, 0.5H), yl)methanone 3.06-2.98 (m, 0.5H),2.96-2.61 (m, 4H). Example 6-[(6- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.32(d, MS 165 chloropyridazin-3- J = 8.1 Hz, 1H), 8.55 (d, J = 8.5 Hz, 1H),(ESI) yl)oxy]-N-(1,1- 8.23 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 8.5 Hz,1H), m/z dioxidotetrahydrothiophen- 8.03 (d, J = 9.2 Hz, 1H), 7.95 (d, J= 2.7 Hz, 419.1 3-yl)quinoline- 1H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H),7.75 (d, J = 9.3 Hz, [M + H]⁺ 2-carboxamide 1H), 4.86-4.76 (m, 1H), 3.51(dd, J = 13.2, 7.7 Hz, 1H), 3.46-3.38 (m, 1H), 3.32 (dd, J = 13.2, 8.8Hz, 1H), 3.27-3.19 (m, 1H), 2.52-2.45 (m, 1H), 2.42-2.31 (m, 1H).Example (3aR,6aR)-5-[(6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS 166(trifluoromethyl)pyridin- 8.62-8.55 (m, 1H), 8.47 (dd, J = 8.5, 4.3 Hz,1H), (ESI) 2- 8.29 (dd, J = 8.7, 2.5 Hz, 1H), 8.15 (dd, J = 9.1, m/zyl]oxy}quinolin-2- 2.4 Hz, 1H), 7.89 (dd, J = 5.9, 2.6 Hz, 443.1yl)carbonyl]hexahydropyrrolo[3, 1H), 7.83 (dd, J = 8.5, 4.5 Hz, 1H),7.79 (s, [M + H]⁺ 4- 1H), 7.72 (td, J = 8.9, 2.6 Hz, 1H), 7.39 (d, J =8.8 Hz, c]pyrrol-1(2H)-one 1H), 4.11 (dd, J = 12.0, 8.8 Hz, 0.5H),4.06-3.93 (m, 1.5H), 3.90 (d, J = 11.4 Hz, 0.5H), 3.74 (dd, J = 12.6,8.2 Hz, 0.5H), 3.57-3.45 (m, 2H), 3.16 (d, J = 10.2 Hz, 0.5H), 3.13-2.97(m, 2.5H). Example (3aR,4R,7S,7aS)- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.58(s, MS 167 octahydro-1H-4,7- 1H), 8.50 (d, J = 8.5 Hz, 0.3H), 8.45 (d, J= 8.5 Hz, (ESI) epiminoisoindol-8- 0.7H), 8.32-8.26 (m, 1H), 8.13 (dd, J= 16.1, m/z yl(6-{[5- 9.1 Hz, 1H), 7.93-7.86 (m, 1H), 7.76 (d, 455.2(trifluoromethyl)pyridin- J = 8.6 Hz, 1H), 7.70 (dd, J = 9.1, 2.6 Hz,1H), [M + H]⁺ 2- 7.43-7.36 (m, 1H), 4.00-3.92 (m, 1.5H),yl]oxy}quinolin-2- 3.33-3.18 (m, 3H), 2.42-2.31 (m, 1.5H), yl)methanone1.90-1.65 (m, 1H), 1.61-1.39 (m, 2.5H), 1.36-1.10 (m, 2.5H). ExampleN-(1,1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.33 (d, MS 168dioxidotetrahydrothiophen- J = 8.1 Hz, 1H), 8.58 (d, J = 8.6 Hz, 1H),(ESI) 3-yl)-6-{[6- 8.38 (d, J = 9.2 Hz, 1H), 8.26 (d, J = 9.2 Hz, 1H),m/z (trifluoromethyl)pyridazin- 8.20 (d, J = 8.5 Hz, 1H), 8.04 (d, J =2.6 Hz, 453.0 3- 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.88 (dd, J = 9.2, [M +H]⁺ yl]oxy}quinoline-2- 2.6 Hz, 1H), 4.88-4.73 (m, 1H), 3.52 (dd, J =13.2, carboxamide 7.7 Hz, 1H), 3.46-3.38 (m, 1H), 3.37-3.30 (m, 1H),3.29-3.18 (m, 1H), 2.53-2.44 (m, 1H), 2.44-2.30 (m, 1H). Example8-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCI m/z 169(trifluoromethyl)pyridin- ppm 2.13-2.36 (m, 1H), 2.39-2.54 (m, 1H),472.0 2- 2.60-3.16 (m, 6H), 3.33 (m, 1H), 3.76 (d, J = 14.1 Hz, [M + H]⁺yl]oxy}quinolin-2- 0.44H), 4.04 (dd, J = 21.4, 9.8 Hz,yl)carbonyl]hexahydro- 0.6H), 4.44-4.62 (m, 0.6H), 4.93 (d, J = 12.3 Hz,2H-pyrazino[1,2- 0.4H), 7.40 (dd, J = 8.7, 3.2 Hz, 1H),a]pyrazin-1(6H)-one 7.64-7.97 (m, 4H), 8.11 (dd, J = 9.1, 4.8 Hz, 1H),8.30 (dt, J = 8.7, 3.1 Hz, 1H), 8.42-8.54 (m, 1H), 8.54-8.67 (m, 1H)Example 5,6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 170dihydro[1,2,4]triazolo[4, 4.01 (dd, J = 8.6, 3.3 Hz, 1H), 4.11-4.30 (m,3H), 441.0 3-a]pyrazin-7(8H)- 5.08 (d, J = 13.3 Hz, 2H), 7.41 (d, J =8.7 Hz, [M + H]⁺ yl(6-{[5- 1H), 7.75 (dd, J = 9.1, 2.6 Hz, 1H),(trifluoromethyl)pyridin- 7.79-7.87 (m, 1H), 7.92 (d, J = 2.6 Hz, 1H),8.16 (d, J = 9.1 Hz, 2- 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H),yl]oxy}quinolin-2- 8.46-8.69 (m, 3H) yl)methanone Example 8-[(6-{[5- ¹HNMR (400 MHz, DMSO-d₆ rotamers) δ DCI m/z 171 (trifluoromethyl)pyridin-ppm 2.92 (m, 2H), 3.10-3.24 (m, 1H), 486.0 2- 3.72-4.05 (m, 2.5H), 4.21(ddd, J = 16.4, 15.9, 11.1 Hz, [M + H]⁺ yl]oxy}quinolin-2- 2H), 4.47 (m,0.58), 4.57 (d, J = 12.6 Hz, yl)carbonyl]tetrahydro- 0.56H), 4.91 (dd, J= 13.0, 1.9 Hz, 0.46H), 2H-pyrazino[1,2- 7.40 (dd, J = 8.7, 3.9 Hz, 1H),7.66-7.84 (m, a]pyrazine- 2H), 7.92 (dd, J = 7.1, 2.6 Hz, 1H), 8.12 (dd,J = 9.1, 1,4(3H,6H)-dione 5.4 Hz, 1H), 8.19-8.43 (m, 2H), 8.52 (t, J =8.3 Hz, 1H), 8.61 (d, J = 9.6 Hz, 1H) Example 4-[(6-{[5- ¹H NMR (400MHz, DMSO-d₆, rotamers) δ DCI m/z 172 (trifluoromethyl)pyridin- ppm,3.34 (m, 2H), 3.69-3.80 (m, 1H), 417.0 2- 3.89 (t, J = 5.4 Hz, 1H), 4.21(d, J = 5.7 Hz, 2H), [M + H]⁺ yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz,1H), 7.67-7.84 (m, 2H), yl)carbonyl]piperazin- 7.90 (d, J = 2.2 Hz, 1H),8.08-8.20 (m, 2H), 2-one 8.30 (dd, J = 8.7, 2.2 Hz, 1H), 8.46-8.63 (m,2H) Example 5,6- ¹H NMR (300 MHz, DMSO-d₆, rotamers) δ DCI m/z 173dihydroimidazo[1,5- ppm 3.85-4.26 (m, 4H), 4.90 (d, J = 17.4 Hz, 440.0a]pyrazin-7(8H)-yl(6- 2H), 6.75 (d, J = 63.7 Hz, 1H), 7.41 (d, J = 8.7Hz, [M + H]⁺ {[5- 1H), 7.47-7.85 (m, 3H), 7.92 (d, J = 2.6 Hz,(trifluoromethyl)pyridin- 1H), 8.15 (d, J = 9.1 Hz, 1H), 8.32 (dd, J =8.8, 2- 2.6 Hz, 1H), 8.42-8.73 (m, 2H) yl]oxy}quinolin-2- yl)methanoneExample N-[2-(pyrrolidin-1- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.71 (t, DCIm/z 174 yl)ethyl]-6-{[5- J = 8.6 Hz, 4H), 2.42 (s, 4H), 2.65 (t, J = 6.7Hz, 431.0 (trifluoromethyl)pyridin- 2H), 3.50 (q, J = 6.5 Hz, 2H), 7.41(d, J = 8.7 Hz, [M + H]⁺ 2- 1H), 7.76 (dd, J = 9.1, 2.6 Hz, 1H),yl]oxy}quinoline-2- 7.93 (d, J = 2.6 Hz, 1H), 8.19 (dd, J = 8.8, 5.1 Hz,carboxamide 2H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), 8.54 (d, J = 8.6 Hz,1H), 8.61 (s, 1H), 8.88 (t, J = 5.9 Hz, 1H) Example N-[2-(piperidin-1-¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 175 yl)ethyl]-6-{[5- 1.35-1.63(m, 6H), 2.42 (s, 4H), 2.47-2.61 (m, 445.0 (trifluoromethyl)pyridin-2H), 3.48 (dd, J = 12.9, 6.5 Hz, 2H), 7.41 (d, J = 8.7 Hz, [M + H]⁺ 2-1H), 7.66-7.79 (m, 1H), 7.93 (d, J = 2.6 Hz, yl]oxy}quinoline-2- 1H),8.18 (d, J = 8.7 Hz, 2H), carboxamide 8.32 (dd, J = 8.7, 2.5 Hz, 1H),8.47-8.64 (m, 2H), 8.88 (t, J = 5.7 Hz, 1H) Example [4- ¹H NMR (300 MHz,DMSO-d₆) δ ppm MS 176 (methylsulfonyl)piperazin- 8.65-8.56 (m, 1H), 8.51(d, J = 8.3 Hz, 1H), (ESI) 1-yl](6-{[5- 8.38-8.23 (m, 1H), 8.13 (d, J =9.1 Hz, 1H), 7.90 (d, m/z (trifluoromethyl)pyridin- J = 2.6 Hz, 1H),7.81-7.66 (m, 2H), 7.40 (d, J = 8.7 Hz, 481.0 2- 1H), 3.90-3.76 (m, 2H),[M + H]⁺ yl]oxy}quinolin-2- 3.70-3.56 (m, 2H), 3.29-3.25 (m, 2H),3.23-3.11 (m, yl)methanone 2H), 2.94 (s, 3H). Example [4- ¹H NMR (300MHz, DMSO-d₆) δ ppm MS 177 (isopropylsulfonyl)piperazin- 8.65-8.56 (m,1H), 8.50 (d, J = 8.6 Hz, 1H), (ESI) 1-yl](6-{[5- 8.30 (dd, J = 8.6, 2.5Hz, 1H), 8.12 (d, J = 9.1 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.90(d, J = 2.6 Hz, 1H), 7.82-7.65 (m, 509.0 2- 2H), 7.39 (d, J = 8.7 Hz,1H), 3.85-3.70 (m, [M + H]⁺ yl]oxy}quinolin-2- 2H), 3.63-3.49 (m, 2H),3.45-3.40 (m, 2H), yl)methanone 3.34-3.30 (m, 2H), 1.25 (d, J = 6.8 Hz,6H). Example [4- ¹H NMR (300 MHz, DMSO-d₆) δ ppm MS 178(phenylsulfonyl)piperazin- 8.61-8.54 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H),(ESI) 1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.05 (d, J = 9.2 Hz,m/z (trifluoromethyl)pyridin- 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.80-7.74(m, 543.1 2- 3H), 7.73-7.64 (m, 4H), 7.38 (d, J = 8.7 Hz, [M + H]⁺yl]oxy}quinolin-2- 1H), 3.85-3.75 (m, 2H), 3.65-3.56 (m, 2H),yl)methanone 3.10-3.03 (m, 2H), 3.01-2.91 (m, 2H). Example[(2R,4S)-2-(2,5- ¹H NMR (300 MHz, DMSO-d₆, rotamers) δ DCI m/z 179difluorophenyl)-4- ppm 2.05-2.38 (m, 1H), 2.64-2.90 (m, 1H), 518.0fluoropyrrolidin-1- 3.90-4.57 (m, 2H), 5.47 (dt, J = 34.0, 27.1 Hz, [M +H]⁺ yl](6-{[5- 1.5H), 5.93-6.11 (m, 0.4H), (trifluoromethyl)pyridin-6.70-7.00 (m, 1H), 7.07-7.53 (m, 3H), 7.64-7.83 (m, 2- 1.5H), 7.91 (t, J= 5.2 Hz, 1H), 8.04 (d, J = 9.0 Hz, yl]oxy}quinolin-2- 1H), 8.20 (d, J =9.0 Hz, 1H), 8.31 (dt, J = 8.8, yl)methanone 3.1 Hz, 0.4H), 8.50 (d, J =8.4 Hz, 1H), 8.61 (dd, J = 1.6, 0.7 Hz, 1H) Example [(2R,4R)-2-(2,5- ¹HNMR (300 MHz, DMSO-d₆, rotamers) δ DCI m/z 180 difluorophenyl)-4- ppm2.05-2.38 (m, 1H), 2.64-2.90 (m, 1H), 518.0 fluoropyrrolidin-1-3.90-4.57 (m, 2H), 5.47 (dt, J = 34.0, 27.1 Hz, [M + H]⁺ yl](6-{[5-1.5H), 5.93-6.11 (m, 0.4H), (trifluoromethyl)pyridin- 6.70-7.00 (m, 1H),7.07-7.53 (m, 3H), 7.64-7.83 (m, 2- 1.5H), 7.91 (t, J = 5.2 Hz, 1H),8.04 (d, J = 9.0 Hz, yl]oxy}quinolin-2- 1H), 8.20 (d, J = 9.0 Hz, 1H),8.31 (dt, J = 8.8, yl)methanone 3.1 Hz, 0.4H), 8.50 (d, J = 8.4 Hz, 1H),8.61 (dd, J = 1.6, 0.7 Hz, 1H) Example [4-(2,2,2- ¹H NMR (300 MHz,DMSO-d₆) δ ppm MS 181 trifluoroethyl)piperazin- 8.60-8.56 (m, 1H), 8.48(d, J = 8.3 Hz, 1H), (ESI) 1-yl](6-{[5- 8.33-8.25 (m, 1H), 8.10 (d, J =9.1 Hz, 1H), 7.89 (d, m/z (trifluoromethyl)pyridin- J = 2.6 Hz, 1H),7.74-7.66 (m, 2H), 7.39 (d, J = 8.6 Hz, 485.1 2- 1H), 3.77-3.67 (m, 2H),[M + H]⁺ yl]oxy}quinolin-2- 3.51-3.45 (m, 2H), 3.25-3.16 (m, 2H),2.79-2.71 (m, yl)methanone 2H), 2.70-2.60 (m, 2H). Example[4-(pyridin-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 182yl)piperazin-1-yl](6- 8.64-8.56 (m, 1H), 8.50 (d, J = 8.3 Hz, 1H), (ESI){[5- 8.30 (dd, J = 8.8, 2.4 Hz, 1H), 8.19-8.08 (m, 2H), m/z(trifluoromethyl)pyridin- 7.90 (d, J = 2.6 Hz, 1H), 7.75 (d, J = 8.5 Hz,480.1 2- 1H), 7.72 (dd, J = 9.1, 2.7 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.63-7.50 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.86 (d,J = 8.6 Hz, yl)methanone 1H), 6.73-6.62 (m, 1H), 3.89-3.77 (m, 2H),3.72-3.64 (m, 2H), 3.64-3.58 (m, 2H), 3.58-3.51 (m, 2H). Example[4-(pyridin-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 183ylsulfonyl)piperazin- 8.96-8.90 (m, 2H), 8.61-8.56 (m, 1H), 8.45 (d, J =8.5 Hz, (ESI) 1-yl](6-{[5- 1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.21-8.15 (m, 1H), 8.07 (d, J = 9.1 Hz, 1H),544.1 2- 7.87 (d, J = 2.6 Hz, 1H), 7.75-7.65 (m, 3H), [M + H]⁺yl]oxy}quinolin-2- 7.38 (d, J = 8.7 Hz, 1H), 3.88-3.74 (m, 2H),yl)methanone 3.68-3.57 (m, 2H), 3.21-3.10 (m, 2H), 3.10-3.00 (m, 2H).Example [4-(piperidin-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 184ylsulfonyl)piperazin- 8.61-8.56 (m, 1H), 8.50 (d, J = 8.5 Hz, 1H), (ESI)1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.77-7.70 (m,550.1 2- 2H), 7.39 (d, J = 8.7 Hz, 1H), 3.82-3.72 (m, [M + H]⁺yl]oxy}quinolin-2- 2H), 3.60-3.53 (m, 2H), 3.30-3.26 (m, 2H),yl)methanone 3.23-3.13 (m, 6H), 1.58-1.46 (m, 6H). Example[4-(morpholin-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 185ylsulfonyl)piperazin- 8.61-8.56 (m, 1H), 8.50 (d, J = 8.5 Hz, 1H), (ESI)1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.77-7.70 (m,552.1 2- 2H), 7.39 (d, J = 8.7 Hz, 1H), 3.82-3.74 (m, [M + H]⁺yl]oxy}quinolin-2- 2H), 3.66-3.53 (m, 6H), 3.40-3.34 (m, 2H),yl)methanone 3.28-3.22 (m, 2H), 3.19-3.12 (m, 4H). Example methyl4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 186(trifluoromethyl)pyridin- 8.61-8.57 (m, 1H), 8.49 (d, J = 8.5 Hz, 1H),(ESI) 2- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.11 (d, J = 9.1 Hz, m/zyl]oxy}quinolin-2- 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.76-7.69 (m, 461.1yl)carbonyl]piperazine- 2H), 7.39 (d, J = 8.7 Hz, 1H), 3.76-3.67 (m,[M + H]⁺ 1-carboxylate 2H), 3.63 (s, 3H), 3.57-3.48 (m, 4H), 3.47-3.38(m, 2H). Example N,N-dimethyl-4-[(6- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90°C.) δ MS 187 {[5- ppm 8.53 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), (APCI)(trifluoromethyl)pyridin- 8.22 (dd, J = 8.7, 2.5 Hz, 1H), 8.12 (d, J =9.1 Hz, m/z 2- 1H), 7.82 (d, J = 2.6 Hz, 1H), 474.2 yl]oxy}quinolin-2-7.75-7.62 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H), 3.71 (s, 4H), [M + H]⁺yl)carbonyl]piperazine- 3.24 (s, 4H), 2.79 (s, 6H). 1-carboxamideExample 5-methyl-8-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS188 (trifluoromethyl)pyridin- ppm 8.58-8.40 (m, 2H), 8.23 (dd, J = 8.7,2.5 Hz, (APCI) 2- 1H), 8.13 (t, J = 10.5 Hz, 1H), 7.83 (dd, J = 16.3,m/z yl]oxy}quinolin-2- 5.4 Hz, 2H), 7.76-7.60 (m, 1H), 473.2yl)carbonyl]-2-oxa- 7.34 (t, J = 7.8 Hz, 1H), 4.89 (d, J = 7.0 Hz, 2H),[M + H]⁺ 5,8- 4.58 (d, J = 7.4 Hz, 2H), 4.33 (d, J = 9.1 Hz,diazaspiro[3.5]nonan- 4H), 3.17 (s, 3H). 6-one Example 2-[(6-{[5- ¹H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 189 (trifluoromethyl)pyridin- ppm8.53 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), (APCI) 2- 8.23 (dd, J = 8.7, 2.5Hz, 1H), 8.13 (d, J = 9.1 Hz, m/z yl]oxy}quinolin-2- 1H), 7.82 (d, J =2.6 Hz, 1H), 458.2 yl)carbonyl]hexahydroimidazo[1, 7.76-7.64 (m, 2H),7.33 (d, J = 8.7 Hz, 1H), [M + H]⁺ 5- 4.81-3.38 (m, 4H), 3.17-2.65 (m,4H). a]pyrazin-3(2H)-one Example (3,3-difluoro-4- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 190 hydroxypiperidin-1- ppm 8.58-8.42 (m, 2H),8.28-8.18 (m, 1H), (APCI) yl)(6-{[5- 8.18-8.07 (m, 1H), 7.84 (dd, J =8.9, 2.1 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.75-7.64 (m, 2H), 7.35(dd, J = 9.3, 4.6 Hz, 454.2 2- 1H), 4.19-3.43 (m, 5H), 2.07-1.83 (m,[M + H]⁺ yl]oxy}quinolin-2- 1H), 1.83-1.69 (m, 1H). yl)methanone Example[cis-3-fluoro-4- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 191hydroxypiperidin-1- ppm 8.57-8.40 (m, 2H), 8.28-8.17 (m, 1H), (APCI)yl](6-{[5- 8.16-8.06 (m, 1H), 7.82 (d, J = 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.74-7.59 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H),436.1 2- 4.93-3.39 (m, 6H), 2.07-1.64 (m, 2H) [M + H]⁺yl]oxy}quinolin-2- yl)methanone Example [cis-4-fluoro-3- ¹H NMR (400MHz, DMSO-d₆/D₂O, 90° C.) δ MS 192 hydroxypiperidin-1- ppm 8.50 (dt, J =29.0, 7.8 Hz, 2H), (APCI) yl](6-{[5- 8.27-8.19 (m, 1H), 8.19-8.06 (m,1H), 7.82 (d, J = 2.6 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.73-7.63(m, 2H), 7.33 (d, J = 8.7 Hz, 436.1 2- 1H), 4.93-4.72 (m, 1H), [M + H]⁺yl]oxy}quinolin-2- 4.14-3.90 (m, 1H), 3.90-3.43 (m, 4H), 2.32-1.71 (m,yl)methanone 2H). Example (4,4-difluoro-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O,90° C.) δ MS 193 hydroxypiperidin-1- ppm 8.53 (s, 1H), 8.47 (d, J = 8.5Hz, 1H), (APCI) yl)(6-{[5- 8.22 (dd, J = 8.7, 2.5 Hz, 1H), 8.12 (d, J =9.1 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.83 (d, J = 2.6 Hz, 1H),454.1 2- 7.77-7.63 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 4.26-3.52 (m, 5H), 2.25 (ddd, J = 30.3, 13.6, 7.0 Hz,yl)methanone 1H), 2.02 (s, 1H). Example [(2S,3R)-3-ethyl-2- ¹H NMR (400MHz, DMSO-d₆/D₂O, 90° C.) δ MS 194 (hydroxymethyl)azetidin- ppm8.62-8.39 (m, 2H), 8.27-8.05 (m, 2H), (APCI) 1-yl](6-{[5- 8.05-7.94 (m,1H), 7.93-7.74 (m, 1H), m/z (trifluoromethyl)pyridin- 7.70 (ddd, J =11.8, 6.8, 2.3 Hz, 1H), 432.2 2- 7.41-7.28 (m, 1H), 5.17-3.45 (m, 5H),3.14-2.65 (m, [M + H]⁺ yl]oxy}quinolin-2- 1H), 1.86-1.47 (m, 2H),1.16-0.78 (m, 3H). yl)methanone Example [trans-3-fluoro-4- ¹H NMR (400MHz, DMSO-d₆/D₂O, 90° C.) δ MS 195 hydroxypiperidin-1- ppm 8.57-8.50 (m,1H), 8.50-8.40 (m, 1H), (APCI) yl](6-{[5- 8.27-8.18 (m, 1H), 8.12 (dd, J= 9.0, 4.9 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.82 (d, J = 2.6 Hz,1H), 7.68 (dd, J = 12.9, 436.1 2- 5.7 Hz, 2H), 7.38-7.28 (m, 1H), [M +H]⁺ yl]oxy}quinolin-2- 4.82-4.24 (m, 1H), 4.10-3.37 (m, 5H),yl)methanone 2.07-1.88 (m, 1H), 1.85-1.48 (m, 1H). Example[trans-4-fluoro-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 196hydroxypiperidin-1- ppm 8.54 (t, J = 4.0 Hz, 1H), 8.46 (d, J = 8.5 Hz,(APCI) yl](6-{[5- 1H), 8.27-8.18 (m, 1H), 8.18-8.07 (m, m/z(trifluoromethyl)pyridin- 1H), 7.83 (t, J = 3.9 Hz, 1H), 7.68 (dd, J =9.0, 436.1 2- 2.6 Hz, 2H), 7.34 (dd, J = 9.2, 5.0 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 4.70-4.44 (m, 1H), 4.41-3.35 (m, 4H), yl)methanone3.26-3.16 (m, 1H), 2.40-1.65 (m, 2H). Example (6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 197 (trifluoromethyl)pyridin- ppm 8.49 (ddd, J= 41.4, 8.3, 5.9 Hz, 2H), (APCI) 2- 8.27-8.19 (m, 1H), 8.19-8.08 (m,1H), m/z yl]oxy}quinolin-2- 8.03-7.91 (m, 1H), 7.85-7.77 (m, 1H), 416.1yl)[(2R)-2,3,3- 7.73-7.62 (m, 1H), 7.34 (t, J = 6.9 Hz, 1H), [M + H]⁺trimethylazetidin-1- 4.76-3.96 (m, 2H), 3.95-3.55 (m, 1H), 1.47-1.08 (m,yl]methanone 9H). Example (3-hydroxy-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O,90° C.) δ MS 198 methylazetidin-1- ppm 8.58-8.40 (m, 2H), 8.23 (dd, J =8.7, 2.5 Hz, (APCI) yl)(6-{[5- 1H), 8.15 (d, J = 9.1 Hz, 1H), 8.03 (d, J= 8.6 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.81 (d, J = 2.6 Hz, 1H),7.68 (dd, 404.1 2- J = 9.1, 2.6 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), [M +H]⁺ yl]oxy}quinolin-2- 4.62-4.29 (m, 2H), 4.24-3.96 (m, 2H),yl)methanone 1.47 (s, 3H). Example [3-(methoxymethyl)- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 199 3-methylazetidin-1- ppm 8.58-8.39 (m, 2H),8.22 (dd, J = 8.7, 2.5 Hz, (APCI) yl](6-{[5- 1H), 8.15 (d, J = 9.1 Hz,1H), 8.03 (d, J = 8.6 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.81 (d, J= 2.6 Hz, 1H), 7.68 (dd, 432.2 2- J = 9.1, 2.6 Hz, 1H), 7.33 (d, J = 8.7Hz, 1H), [M + H]⁺ yl]oxy}quinolin-2- 4.61-4.50 (m, 1H), 4.35 (d, J = 9.8Hz, 1H), yl)methanone 4.04-3.93 (m, 1H), 3.76 (d, J = 9.9 Hz, 1H), 3.42(s, 2H), 3.35 (s, 3H), 1.30 (s, 3H). Example (3-methyl-3- ¹H NMR (400MHz, DMSO-d₆/D₂O, 90° C.) δ MS 200 phenoxyazetidin-1- ppm 8.54 (s, 1H),8.47 (d, J = 8.6 Hz, 1H), (APCI) yl)(6-{[5- 8.23 (dd, J = 8.7, 2.5 Hz,1H), 8.19 (d, J = 9.1 Hz, m/z (trifluoromethyl)pyridin- 1H), 8.05 (d, J= 8.5 Hz, 1H), 7.82 (d, J = 2.6 Hz, 480.1 2- 1H), 7.69 (dd, J = 9.1, 2.6Hz, 1H), [M + H]⁺ yl]oxy}quinolin-2- 7.33 (t, J = 8.0 Hz, 3H), 7.01 (t,J = 7.4 Hz, yl)methanone 1H), 6.87 (d, J = 7.8 Hz, 2H), 4.90 (d, J = 9.6Hz, 2H), 4.32 (d, J = 10.5 Hz, 2H), 1.71 (s, 3H). Example(3-phenoxyazetidin- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 2011-yl)(6-{[5- ppm 8.58-8.42 (m, 2H), 8.22 (dd, J = 8.8, 2.3 Hz, (APCI)(trifluoromethyl)pyridin- 1H), 8.17 (d, J = 9.1 Hz, 1H), 8.05 (d, J =8.6 Hz, m/z 2- 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.68 (dd, 466.2yl]oxy}quinolin-2- J = 9.1, 2.6 Hz, 1H), 7.40-7.27 (m, 3H), [M + H]⁺yl)methanone 7.01 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 5.18(s, 2H), 4.66 (d, J = 30.9 Hz, 2H), 4.12 (s, 1H). Example[3-(1H-imidazol-1- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 202yl)azetidin-1-yl](6- ppm 9.23 (s, 1H), 8.57-8.45 (m, 2H), (APCI) {[5-8.24 (dd, J = 8.7, 2.4 Hz, 1H), 8.17 (d, J = 9.2 Hz, m/z(trifluoromethyl)pyridin- 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H),440.1 2- 7.84 (d, J = 2.6 Hz, 1H), 7.76-7.62 (m, 2H), [M + H]⁺yl]oxy}quinolin-2- 7.34 (d, J = 8.7 Hz, 1H), 5.59-5.46 (m, 1H),yl)methanone 4.92 (dd, J = 243.8, 109.1 Hz, 4H). Example [3-(4- H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 203 chlorophenoxy)azetidin- ppm8.58-8.42 (m, 2H), 8.23 (dd, J = 8.7, 2.4 Hz, (APCI) 1-yl](6-{[5- 1H),8.17 (d, J = 9.1 Hz, 1H), 8.05 (d, J = 8.5 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.68 (dd, 500.12- J = 9.1, 2.6 Hz, 1H), 7.40-7.28 (m, 3H), [M + H]⁺ yl]oxy}quinolin-2-6.99-6.88 (m, 2H), 5.17 (s, 2H), 4.66 (d, J = 25.1 Hz, yl)methanone 2H),4.12 (s, 1H). Example [3-(1H-1,2,4-triazol- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 204 1-yl)azetidin-1-yl](6- ppm 8.67-8.58 (m,1H), 8.58-8.39 (m, 2H), (APCI) {[5- 8.23 (dd, J = 8.7, 2.4 Hz, 1H),8.19-8.02 (m, m/z (trifluoromethyl)pyridin- 3H), 7.82 (dd, J = 7.1, 2.6Hz, 1H), 7.67 (ddd, 441.2 2- J = 12.3, 7.5, 4.2 Hz, 1H), 7.33 (d, J =8.7 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 5.54 (tdd, J = 10.3, 6.5, 3.4Hz, 1H), yl)methanone 5.34-4.87 (m, 2H), 4.87-4.58 (m, 1H), 4.57-4.38(m, 1H). Example (6-{[5- ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 205(trifluoromethyl)pyridin- 8.58-8.39 (m, 2H), 8.22 (dd, J = 8.7, 2.6 Hz,(APCI) 2- 1H), 8.14 (d, J = 9.1 Hz, 1H), 7.98 (s, 1H), m/zyl]oxy}quinolin-2- 7.81 (d, J = 2.6 Hz, 1H), 7.73-7.62 (m, 1H), 416.1yl)[(2S)-2,3,3- 7.33 (d, J = 8.8 Hz, 1H), 4.76-3.40 (m, 3H), [M + H]⁺trimethylazetidin-1- 1.45-1.14 (m, 9H). yl]methanone Example [3-(4- ¹HNMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 206 bromophenoxy)azetidin- ppm8.58-8.42 (m, 2H), 8.23 (dd, J = 8.6, 2.4 Hz, (APCI) 1-yl](6-{[5- 1H),8.17 (d, J = 9.1 Hz, 1H), 8.05 (d, J = 8.6 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.68 (dd, 544.02- J = 9.1, 2.6 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), [M + H]⁺yl]oxy}quinolin-2- 7.33 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.9 Hz,yl)methanone 2H), 5.17 (s, 2H), 4.65 (d, J = 32.2 Hz, 2H), 4.12 (s, 1H).Example [3-(hydroxymethyl)- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS207 3-methylazetidin-1- ppm 8.58-8.39 (m, 2H), 8.22 (dd, J = 8.7, 2.5Hz, (APCI) yl](6-{[5- 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.03 (dd, J = 8.5,m/z (trifluoromethyl)pyridin- 4.1 Hz, 1H), 7.81 (d, J = 2.6 Hz, 1H),418.1 2- 7.68 (dd, J = 9.1, 2.6 Hz, 1H), 7.38-7.28 (m, 1H), [M + H]⁺yl]oxy}quinolin-2- 4.60-4.38 (m, 1H), 4.31 (d, J = 9.9 Hz, 1H),yl)methanone 4.00 (dd, J = 10.3, 5.4 Hz, 1H), 3.93-3.60 (m, 1H), 3.47(s, 2H), 1.28 (s, 3H). Example 3-phenyl-4-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm MS 208 (trifluoromethyl)pyridin- 8.57-8.41 (m, 2H), 8.22(dd, J = 8.7, 2.5 Hz, 2H), (APCI) 2- 7.86-7.06 (m, 11H), 6.05 (s, 1H),m/z yl]oxy}quinolin-2- 4.40-3.42 (m, 3H). 493.2 yl)carbonyl]piperazin-[M + H]⁺ 2-one Example {6-[4-(2- ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45(s, DCI m/z 209 hydroxypropan-2- 6H), 2.62-2.70 (m, 2H), 2.75-2.84 (m,2H), 392.0 yl)phenoxy]quinolin- 3.34 (dd, J = 9.1, 4.2 Hz, 2H),3.52-3.69 (m, [M + H]⁺ 2-yl}(piperazin-1- 2H), 5.03 (s, 1H), 7.01-7.13(m, 2H), 7.44 (d, yl)methanone J = 2.7 Hz, 1H), 7.48-7.69 (m, 4H), 8.05(d, J = 9.2 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H) Example 6-{[5- ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.40 (d, DCI m/z 210 (trifluoromethyl)pyridin- J =8.7 Hz, 1H), 7.68-7.85 (m, 2H), 7.92 (d, J = 2.5 Hz, 334.0 2- 1H), 8.18(dd, J = 8.8, 4.0 Hz, 2H), [M + H]⁺ yl]oxy}quinoline-2- 8.24-8.38 (m,2H), 8.52 (d, J = 8.6 Hz, 1H), carboxamide 8.61 (s, 1H) Example(4-methylpiperazin-1- ¹H NMR (300 MHz, DMSO-d₆) δ ppm MS 211 yl)(6-{[5-8.61-8.55 (m, 1H), 8.48 (d, J = 8.5 Hz, 1H), (ESI)(trifluoromethyl)pyridin- 8.30 (dd, J = 8.8, 2.6 Hz, 1H), 8.11 (d, J =9.1 Hz, m/z 2- 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.74-7.66 (m, 417.1yl]oxy}quinolin-2- 2H), 7.39 (d, J = 8.8 Hz, 1H), 3.75-3.66 (m, [M + H]⁺yl)methanone 2H), 3.50-3.39 (m, 2H), 2.46-2.39 (m, 2H), 2.36-2.27 (m,2H), 2.22 (s, 3H). Example (8S,9aS)-8-hydroxy- ¹H NMR (300 MHz, DMSO-d₆,rotamers) δ DCI m/z 212 2-[(6-{[5- ppm 1.33-1.58 (m, 0.58H), 1.67-1.87(m, 487.0 (trifluoromethyl)pyridin- 0.55H), 2.13-2.44 (m, 2H), 2.53-2.66(m, [M + H]⁺ 2- 0.3H), 2.65-3.10 (m, 1.68H), 3.10-3.4 (m,yl]oxy}quinolin-2- 2H), 3.32-3.40 (m, 0.4H), 3.42-3.58 (m,yl)carbonyl]octahydro- 0.8H), 3.73-3.94 (m, 1H), 3.97-4.38 (m,5H-pyrrolo[1,2- 2H), 4.49-4.76 (m, 1H), 4.95 (d, J = 3.2 Hz,a][1,4]diazepin-5-one 0.5H), 5.10 (dd, J = 7.4, 3.0 Hz, 0.5H), 7.28-7.50(m, 1H), 7.67-7.80 (m, 2H), 7.90 (t, J = 2.8 Hz, 1H), 8.05-8.16 (m, 1H),8.24-8.36 (m, 1H), 8.50 (dd, J = 8.5, 4.0 Hz, 1H), 8.54-8.65 (m, 1H)Example (1S,6R)-3,8- ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ DCI m/z 213diazabicyclo[4.2.0]oct- ppm 1.66-1.95 (m, 1.4H), 1.95-2.06 (m, 429.03-yl(6-{[5- 0.6H), 2.70 (dd, J = 25.7, 10.2 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 2.93-3.17 (m, 1.4H), 3.23-3.41 (m, 3.6H), 3.66(dt, 2- J = 33.3, 7.6 Hz, 1H), 3.84-3.97 (m, 1H), yl]oxy}quinolin-2-4.00-4.18 (m, 1H), 7.39 (dd, J = 8.7, 4.2 Hz, yl)methanone 1H),7.65-7.80 (m, 2H), 7.89 (dd, J = 8.2, 2.6 Hz, 1H), 8.04-8.17 (m, 1H),8.30 (dd, J = 8.7, 2.3 Hz, 1H), 8.46 (dt, J = 15.5, 7.7 Hz, 1H), 8.57(d, J = 10.8 Hz, 1H) Example {6-[4- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCIm/z 214 (methylsulfonyl)phenoxy]quinolin- 2.50 (dd, J = 7.0, 5.2 Hz,1H), 2.62-2.73 (m, 2H), 412.0 2- 2.75-2.84 (m, 2H), 3.23 (s, 3H), [M +H]⁺ yl}(piperazin-1- 3.33-3.46 (m, 2H), 3.55-3.68 (m, 2H), 7.24-7.38 (m,yl)methanone 2H), 7.62-7.71 (m, 2H), 7.75 (d, J = 2.7 Hz, 1H), 7.89-8.02(m, 2H), 8.13 (d, J = 9.1 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H) Examplepiperazin-1-yl(6-{4- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 215[(trifluoromethyl)sulfonyl]phenoxy}quinolin- 2.64-2.72 (m, 2H),2.76-2.89 (m, 2H), 466.0 2-yl)methanone 3.31-3.42 (m, 2H), 3.59-3.66 (m,2H), 7.29-7.49 (m, [M + H]⁺ 2H), 7.65-7.82 (m, 2H), 7.94 (d, J = 2.7 Hz,1H), 8.16 (dt, J = 11.8, 6.0 Hz, 3H), 8.50 (d, J = 8.5 Hz, 1H) ExampleN-(azetidin-3-yl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (d, MS 216{[5- J = 7.8 Hz, 1H), 8.64-8.58 (m, 1H), 8.53 (d, J = 8.5 Hz, (ESI)(trifluoromethyl)pyridin- 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), m/z 2-8.24 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 8.5 Hz, 389.2 yl]oxy}quinoline-2-1H), 7.92 (d, J = 2.6 Hz, 1H), 7.77 (dd, J = 9.1, [M + H]⁺ carboxamide2.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 4.84-4.72 (m, 1H), 3.70 (t, J =7.6 Hz, 2H), 3.61 (t, J = 7.8 Hz, 2H). Example [3-(pyridin-3- ¹H NMR(400 MHz, DMSO-d₆) δ ppm MS 217 yl)azetidin-1-yl](6- 8.65-8.58 (m, 2H),8.53-8.47 (m, 2H), 8.30 (dd, J = 8.8, (ESI) {[5- 2.5 Hz, 1H), 8.17 (d, J= 9.1 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.10 (d, J = 8.6 Hz, 1H),7.98-7.93 (m, 1H), 451.1 2- 7.90 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 9.1,2.6 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 7.44-7.37 (m, 2H), 5.22 (t, J =9.6 Hz, yl)methanone 1H), 4.81 (dd, J = 10.3, 6.4 Hz, 1H), 4.59 (t, J =9.6 Hz, 1H), 4.20 (dd, J = 10.2, 6.4 Hz, 1H), 4.13-4.04 (m, 1H). Example1-{4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.03 ESI m/z 218(trifluoromethyl)pyridin- and 2.07 (2s, 3 H), 3.46-3.52 (m, 3 H) 445.12- 3.54-3.62 (m, 3 H) 3.68 (d, J = 5.80 Hz, 1 H) [M + H]⁺yl]oxy}quinolin-2- 3.72-3.78 (m, 1 H) 7.40 (d, J = 8.54 Hz, 1 H)yl)carbonyl]piperazin- 7.70-7.77 (m, 2 H) 7.90 (s, 1 H) 8.12 (d, J =8.85 Hz, 1-yl}ethanone 1 H) 8.31 (dd, J = 8.70, 2.59 Hz, 1 H) 8.50 (d, J= 8.54 Hz, 1 H) 8.60 (s, 1 H) Example 1,4-diazepan-1-yl(6- ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.60 (s, ESI m/z 219 {[5- 1H), 8.52 (dd, J = 15.2,6.5 Hz, 1H), 451.1 (trifluoromethyl)pyridin- 8.41-8.29 (m, 2H), 8.26 (s,1H), 8.14 (dd, J = 9.1, [M + H]⁺ 2- 5.0 Hz, 1H), 7.92 (d, J = 2.4 Hz,1H), yl]oxy}quinolin-2- 7.83-7.69 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H),7.24 (d, yl)methanone J = 4.9 Hz, 1H), 4.93 (s, 1H), 4.81 (s, 1H), 3.74(t, J = 5.8 Hz, 1H), 3.08 (s, 1H), 3.02 (m, 2H). Example 2,5-dihydro-1H-¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 220 pyrrol-1-yl(6-{[5- 8.60 (dd,J = 2.5, 1.3 Hz, 1H), 8.49 (d, J = 8.5 Hz, 386.1(trifluoromethyl)pyridin- 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.17 (d,J = 9.0 Hz, [M + H]⁺ 2- 1H), 7.95-7.88 (m, 2H), 7.73 (dd, J = 9.0,yl]oxy}quinolin-2- 2.6 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), yl)methanone5.99 (dt, J = 6.4, 2.1 Hz, 1H), 5.98-5.91 (m, 1H), 4.70-4.64 (m, 2H),4.43-4.35 (m, 2H). Example thiomorpholin-4-yl(6- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 221 {[5- 8.61-8.57 (m, 1H), 8.49 (d, J = 8.4 Hz,1H), 420.0 (trifluoromethyl)pyridin- 8.31 (dd, J = 8.7, 2.6 Hz, 1H),8.12 (d, J = 9.0 Hz, [M + H]⁺ 2- 1H), 7.89 (d, J = 2.6 Hz, 1H),7.75-7.68 (m, yl]oxy}quinolin-2- 2H), 7.39 (d, J = 8.6 Hz, 1H), 3.99 (m,2H), yl)methanone 3.67 (m, 2H), 2.75 (m, 2H), 2.71-2.66 (m, 2H). Example3,4-dihydro-2,7- ¹H NMR (500 MHz, DMSO-d₆) δ ppm ESI m/z 222naphthyridin-2(1H)- 8.62-8.57 (m, 1H), 8.55-8.47 (m, 2H), 451.1yl(6-{[5- 8.40-8.28 (m, 2H), 8.14 (dd, J = 9.1, 5.0 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.92 (d, J = 2.5 Hz, 1H), 7.81-7.71 (m, 2H),2- 7.44-7.38 (m, 1H), 7.27-7.21 (m, 1H), 4.93 (s, yl]oxy}quinolin-2-1H), 4.81 (s, 1H), 3.96 (t, J = 6.0 Hz, 1H), yl)methanone 3.74 (t, J =5.8 Hz, 1H), 3.00-2.92 (m, 2H). Example [(2R,4S)-2-(2,5- ¹H NMR (400MHz, DMSO-d₆, rotamers) δ MS 223 difluorophenyl)-4- ppm 8.63-8.58 (m,1H), 8.49 (d, J = 8.5 Hz, (ESI) hydroxypyrrolidin-1- 0.65H), 8.34-8.27(m, 1H), 8.22-8.17 (m, m/z yl](6-{[5- 1H), 7.95 (d, J = 9.1 Hz, 0.35H),7.91 (d, J = 2.6 Hz, 516.0 (trifluoromethyl)pyridin- 0.65H), 7.88 (d, J= 8.5 Hz, 0.65H), [M + H]⁺ 2- 7.77-7.72 (m, 1H), 7.68 (dd, J = 9.1, 2.6Hz, yl]oxy}quinolin-2- 0.35H), 7.50 (d, J = 8.5 Hz, 0.35H), 7.40 (d, J =8.7 Hz, yl)methanone 0.65H), 7.36 (d, J = 8.7 Hz, 0.35H), 7.30-7.19 (m,1.35H), 7.17-7.09 (m, 0.65H), 6.92-6.86 (m, 0.35H), 6.83-6.77 (m,0.65H), 6.00 (t, J = 8.0 Hz, 0.35H), 5.42 (t, J = 8.4 Hz, 0.65H), 5.27(d, J = 3.0 Hz, 0.35H), 5.08 (d, J = 3.1 Hz, 0.65H), 4.44 (s, 0.35H),4.34 (s, 0.65H), 4.22 (dd, J = 11.9, 3.5 Hz, 0.65H), 3.94 (dd, J = 12.5,4.0 Hz, 0.35H), 3.86 (d, J = 12.5 Hz, 0.35H), 3.74 (d, J = 12.0 Hz,0.65H), 2.43-2.34 (m, 1H), 2.04-1.90 (m, 1H). Example {2-[4- ¹H NMR (500MHz, DMSO-d₆, rotamers) δ MS 224 (trifluoromethyl)phenyl]pyrrolidin- ppm8.61-8.55 (m, 1H), 8.48 (d, J = 8.5 Hz, (ESI) 1-yl}(6- 0.6H), 8.29 (ddd,J = 13.7, 8.7, 2.5 Hz, 1H), m/z {[5- 8.21 (dd, J = 18.1, 8.8 Hz, 1H),7.90 (d, J = 2.6 Hz, 532.1 (trifluoromethyl)pyridin- 0.4H), 7.84 (d, J =8.5 Hz, 0.6H), 7.77 (d, [M + H]⁺ 2- J = 9.1 Hz, 0.4H), 7.75-7.69 (m,2H), yl]oxy}quinolin-2- 7.65-7.60 (m, 1H), 7.57 (d, J = 8.2 Hz, 1H),7.49 (d, yl)methanone J = 8.2 Hz, 1H), 7.40 (d, J = 8.7 Hz, 0.6H), 7.35(d, J = 8.7 Hz, 0.4H), 7.29 (d, J = 8.1 Hz, 1H), 5.95-5.85 (m, 0.4H),5.33 (dd, J = 7.8, 5.2 Hz, 0.6H), 4.19-4.10 (m, 0.6H), 3.97-3.81 (m,1.4H), 2.48-2.39 (m, 1H), 2.01-1.76 (m, 3H). ExampleN-{(2R,3S)-2-phenyl- ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ MS 2251-[(6-{[5- ppm 8.76-8.68 (m, 1H), 8.59 (d, J = 13.8 Hz, (ESI)(trifluoromethyl)pyridin- 1H), 8.49 (d, J = 8.5 Hz, 0.5H), m/z 2-8.33-8.27 (m, 1H), 8.19 (dd, J = 8.9, 3.1 Hz, 1H), 687.1yl]oxy}quinolin-2- 8.00 (d, J = 8.3 Hz, 1H), 7.97-7.89 (m, 2.5H), [M +H]⁺ yl)carbonyl]pyrrolidin- 7.84 (d, J = 8.5 Hz, 0.5H), 7.78 (d, J = 8.4Hz, 3-yl}-4- 1H), 7.76-7.71 (m, 1H), 7.65-7.62 (m, 1H),(trifluoromethyl)benzenesulfonamide 7.58 (d, J = 8.5 Hz, 0.5H), 7.40 (d,J = 8.7 Hz, 0.5H), 7.36 (d, J = 8.7 Hz, 0.5H), 7.31-7.25 (m, 1H),7.23-7.18 (m, 0.5H), 7.17 (d, J = 7.3 Hz, 1H), 7.08-6.98 (m, 1.5H), 6.87(d, J = 6.7 Hz, 1H), 5.69 (d, J = 2.8 Hz, 0.5H), 5.13 (d, J = 3.1 Hz,0.5H), 4.31-4.22 (m, 0.5H), 4.07-3.87 (m, 1.5H), 3.68 (d, J = 30.8 Hz,1H), 2.12-1.98 (m, 1H), 1.90-1.73 (m, 1H). Example 1-(6-{[2-(piperazin-¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.58 (s, DCI m/z 226 1- 3H), 2.64-2.70(m, 2H), 2.75-2.86 (m, 2H), 377.0 ylcarbonyl)quinolin- 3.57-3.70 (m,2H), 7.28 (d, J = 8.5 Hz, 1H), [M + H]⁺ 6-yl]oxy}pyridin-3- 7.63-7.76(m, 2H), 7.87 (d, J = 2.6 Hz, 1H), yl)ethanone 8.10 (d, J = 9.1 Hz, 1H),8.38 (dd, J = 8.7, 2.5 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.77 (d, J =2.3 Hz, 1H) Example (1,1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 227dioxidothiomorpholin- 3.33 (m, 4H), 3.87-3.97 (m, 2H), 4.08-4.18 (m,452.0 4-yl)(6-{[5- 2H), 7.40 (d, J = 8.7 Hz, 1H), 7.74 (dd, J = 9.1,[M + H]⁺ (trifluoromethyl)pyridin- 2.7 Hz, 1H), 7.83 (d, J = 8.5 Hz,1H), 7.91 (d, J = 2.6 Hz, 2- 1H), 8.14 (d, J = 9.1 Hz, 1H),yl]oxy}quinolin-2- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.52 (d, J = 8.5 Hz,yl)methanone 1H), 8.59 (dd, J = 1.6, 0.8 Hz, 1H) Example (4-tert- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.02 (s, DCI m/z 228 butylpiperazin-1- 9H),2.47 (s, 2H), 2.56-2.64 (m, 2H), 459.0 yl)(6-{[5- 3.38-3.48 (m, 2H),3.60-3.75 (m, 2H), 7.39 (d, J = 8.6 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 7.62-7.76 (m, 2H), 7.89 (d, J = 2.6 Hz,2- 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.30 (dd, yl]oxy}quinolin-2- J = 8.7,2.5 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), yl)methanone 8.59 (d, J = 1.6 Hz,1H) Example {6-[(5-fluoropyridin- ¹H NMR (300 MHz, DMSO-d₆) δ ppm MS 2292-yl)oxy]quinolin-2- 8.94 (br s, 2H), 8.49 (d, J = 8.6 Hz, 1H), 8.19 (d,(ESI) yl}(piperazin-1- J = 3.1 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), m/zyl)methanone 7.89-7.94 (m, 1H), 7.75-7.77 (m, 2H), 7.67 (dd, 353.2 J =9.2, 2.8 Hz, 1H), 7.28 (dd, J = 8.9, 3.7 Hz, [M + H]⁺ 1H), 3.90-3.93 (m,2H), 3.80-3.82 (m, 2H), 3.18-3.28 (m, 4H). Example N-[(3aS,4R,6aR)-2- ¹HNMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 230benzyloctahydrocyclopenta[c]pyrrol- 1.32-1.50 (m, 1H), 1.59-1.76 (m,1H), 533.0 4-yl]- 1.88-2.07 (m, 2H), 2.14-2.35 (m, 2H), 2.41-2.50 (m,[M + H]⁺ 6-{[5- 1H), 2.54-2.81 (m, 3H), 3.47-3.66 (m, 2H),(trifluoromethyl)pyridin- 4.04-4.27 (m, 1H), 7.20-7.28 (m, 1H), 2-7.30-7.37 (m, 4H), 7.41 (dd, J = 12.0, 5.7 Hz, 1H), yl]oxy}quinoline-2-7.70-7.80 (m, 1H), 7.87-7.97 (m, 1H), carboxamide 8.11-8.18 (m, 1H),8.18-8.24 (m, 1H), 8.27-8.37 (m, 1H), 8.47-8.56 (m, 1H), 8.58-8.66 (m,1H), 8.71 (t, J = 7.3 Hz, 1H) Example (4- ¹H NMR (500 MHz, DMSO-d₆) δppm 0.98 (d, DCI m/z 231 isopropylpiperazin-1- J = 6.5 Hz, 6H), 2.40 (d,J = 33.9 Hz, 2H), 445.0 yl)(6-{[5- 2.55 (s, 2H), 2.79 (dd, J = 67.3,21.3 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 3.38-3.50 (m, 2H), 3.70(s, 2H), 7.39 (d, J = 8.7 Hz, 2- 1H), 7.61-7.78 (m, 2H), 7.89 (d, J =2.6 Hz, yl]oxy}quinolin-2- 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.30 (dd, J =8.7, yl)methanone 2.5 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.53-8.64 (m,1H) Example 2,7- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 232diazaspiro[3.5]non-2- 1.49-1.80 (m, 4H), 2.65 (s, 4H), 3.82 (s, 2H),443.0 yl(6-{[5- 4.42 (s, 2H), 7.40 (d, J = 8.7 Hz, 1H), 7.72 (dd, J =9.1, [M + H]⁺ (trifluoromethyl)pyridin- 2.7 Hz, 1H), 7.89 (d, J = 2.6Hz, 1H), 2- 8.06 (dd, J = 8.6, 5.2 Hz, 1H), 8.18 (t, J = 7.5 Hz,yl]oxy}quinolin-2- 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.48 (d, J = 8.6Hz, yl)methanone 1H), 8.53-8.65 (m, 1H) Example tetrahydropyrimidin- ¹HNMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 233 1(2H)-yl(6-{[5- 1.61 (dd, J =34.5, 23.7 Hz, 2H), 2.80-2.95 (m, 403.0 (trifluoromethyl)pyridin- 2H),3.48-3.90 (m, 2H), 4.44 (d, J = 88.4 Hz, [M + H]⁺ 2- 2H), 7.39 (d, J =8.7 Hz, 1H), 7.62-7.81 (m, yl]oxy}quinolin-2- 2H), 7.89 (d, J = 2.6 Hz,1H), 8.11 (t, J = 8.7 Hz, yl)methanone 1H), 8.30 (dd, J = 8.7, 2.5 Hz,1H), 8.48 (d, J = 8.5 Hz, 1H), 8.59 (s, 1H) Example [(2S)-2- ¹H NMR (500MHz, DMSO-d₆ rotamers) δ DCI m/z 234 (hydroxymethyl)piperazin- ppm2.53-2.80 (m, 2.8H), 2.92 (ddd, J = 37.7, 433.0 1-yl](6-{[5- 29.2, 12.4Hz, 2.3H), 3.16 (t, J = 13.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H),3.46-3.65 (m, 1H), 3.68-3.83 (m, 2- 1.4H), 3.88 (t, J = 9.5 Hz, 0.4H),4.23 (dd, J = 23.5, yl]oxy}quinolin-2- 19.8 Hz, 0.7H), 4.46 (s, 0.4H),4.75 (s, yl)methanone 0.6H), 7.39 (d, J = 8.7 Hz, 1H), 7.57-7.75 (m,2H), 7.87 (d, J = 2.6 Hz, 1H), 8.10 (dd, J = 12.3, 9.2 Hz, 1H), 8.30(dd, J = 8.7, 2.4 Hz, 1H), 8.46 (t, J = 8.3 Hz, 1H), 8.59 (s, 1H)Example N-methyl-4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 235(trifluoromethyl)pyridin- 8.62-8.57 (m, 1H), 8.50 (d, J = 8.5 Hz, 1H),(ESI) 2- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, m/zyl]oxy}quinolin-2- 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.77-7.70 (m, 496.0yl)carbonyl]piperazine- 2H), 7.39 (d, J = 8.7 Hz, 1H), 7.22 (q, J = 4.9Hz, [M + H]⁺ 1-sulfonamide 1H), 3.85-3.75 (m, 2H), 3.64-3.53 (m, 2H),3.24-3.18 (m, 2H), 3.15-3.08 (m, 2H), 2.57 (d, J = 4.9 Hz, 3H). ExampleN-ethyl-4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 236(trifluoromethyl)pyridin- 8.61-8.57 (m, 1H), 8.50 (d, J = 8.5 Hz, 1H),(ESI) 2- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.12 (d, J = 9.1 Hz, m/zyl]oxy}quinolin-2- 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.77-7.69 (m, 509.9yl)carbonyl]piperazine- 2H), 7.39 (d, J = 8.7 Hz, 1H), 7.31 (t, J = 5.7Hz, [M + H]⁺ 1-sulfonamide 1H), 3.84-3.76 (m, 2H), 3.62-3.52 (m, 2H),3.22-3.14 (m, 2H), 3.13-3.05 (m, 2H), 3.01-2.92 (m, 2H), 1.08 (t, J =7.2 Hz, 3H). Example [(2S)-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (s,ESI m/z 237 (hydroxymethyl)pyrrolidin- 1H), 8.46 (d, J = 8.6 Hz, 1H),8.30 (dd, J = 8.8, 418.0 1-yl](6-{[5- 2.5 Hz, 1H), 8.13 (dd, J = 9.1,3.2 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 7.94-7.63 (m, 3H), 7.39(d, J = 8.7 Hz, 1H), 2- 4.80 (m, 1H), 4.39 (m, 1H), 3.51-3.74 (m, 3H),yl]oxy}quinolin-2- 3.14 (m, 1H), 1.96-1.78 (m, 4H). yl)methanone Exampleazepan-1-yl(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (d, ESI m/z 238(trifluoromethyl)pyridin- J = 0.8 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H),416.2 2- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.09 (d, J = 9.1 Hz, [M + H]⁺yl]oxy}quinolin-2- 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.76-7.61 (m,yl)methanone 2H), 7.39 (d, J = 8.7 Hz, 1H), 3.71-3.59 (m, 2H), 3.42 (t,J = 5.7 Hz, 2H), 1.78 (dd, J = 11.5, 5.7 Hz, 2H), 1.71-1.45 (m, 6H).Example N-methyl-1-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 239(trifluoromethyl)pyridin- 8.60 (bs, 1H), 8.50-8.39 (m, 1H), 8.30 (dd, J= 8.7, 445.1 2- 2.3 Hz, 1H), 8.11 (dd, J = 37.5, 9.1 Hz, [M + H]⁺yl]oxy}quinolin-2- 1H), 7.95-7.81 (m, 2H), 7.83-7.68 (m, 2H),yl)carbonyl]-L- 7.39 (dd, J = 8.7, 4.3 Hz, 1H), 4.98 and prolinamide4.50 (2m, 1H), 3.89 and 3.72 (2m, 2H), 2.63 and 2.40 (2d, J = 4.5 Hz,3H), 2.29-2.11 (m, 2H), 1.90 (m, 2H). Example 1,4-dioxa-8- ¹H NMR (500MHz, DMSO-d₆) δ ppm ESI m/z 240 azaspiro[4.5]dec-8- 8.61-8.57 (m, 1H),8.48 (d, J = 8.4 Hz, 1H), 460.0 yl(6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz,1H), 8.11 (d, J = 9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.89(d, J = 2.6 Hz, 1H), 7.74-7.68 (m, 2- 2H), 7.39 (d, J = 8.7 Hz, 1H),3.98-3.87 (m, yl]oxy}quinolin-2- 4H), 3.77 (t, J = 5.5 Hz, 2H), 3.47 (t,J = 5.3 Hz, yl)methanone 2H), 1.78-1.72 (m, 2H), 1.69 (t, J = 5.4 Hz,2H). Example (1R,4R)-2,5- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ MS 241diazabicyclo[2.2.1]hept- ppm 8.59 (s, 1H), 8.50-8.44 (m, 1H), (ESI)2-yl(6-{[5- 8.30 (dd, J = 8.7, 2.4 Hz, 1H), 8.12 (d, J = 9.1 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.93-7.87 (m, 1.5H), 7.85 (d, J = 8.5 Hz,415.2 2- 0.5H), 7.74-7.68 (m, 1H), 7.39 (d, J = 8.6 Hz, [M + H]⁺yl]oxy}quinolin-2- 1H), 4.88 (s, 0.5H), 4.80 (s, 0.5H), yl)methanone3.88 (dd, J = 10.4, 2.1 Hz, 0.5H), 3.69-3.58 (m, 1.5H), 3.52 (dd, J =11.1, 2.0 Hz, 1H), 3.38 (d, J = 11.1 Hz, 1H), 3.11 (d, J = 9.6 Hz, 1H),2.95-2.89 (m, 1H), 1.81-1.73 (m, 1H), 1.68-1.57 (m, 1H). Examplepiperazin-1-yl[6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 242 (pyrimidin-2-8.93 (br s, 2H), 8.69 (d, J = 4.9 Hz, 2H), 8.52 (d, (ESI)yloxy)quinolin-2- J = 8.5 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.91 (d,m/z yl]methanone J = 2.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 336.1 7.75(dd, J = 9.0, 2.6 Hz, 1H), 7.34 (t, J = 4.7 Hz, 1H), [M + H]⁺ 3.91-3.93(m, 2H), 3.80-3.81 (m, 2H), 3.28-3.30 (m, 2H), 3.17-3.19 (m, 2H).Example [(2R)-2- ¹H NMR (500 MHz, DMSO-d₆ rotamers) δ DCI m/z 243(hydroxymethyl)piperazin- ppm 2.53-2.80 (m, 2.8H), 2.92 (ddd, J = 37.7,433.0 1-yl](6-{[5- 29.2, 12.4 Hz, 2.3H), 3.16 (t, J = 13.0 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 3.46-3.65 (m, 1H), 3.68-3.83 (m, 2-1.4H), 3.88 (t, J = 9.5 Hz, 0.4H), 4.23 (dd, J = 23.5,yl]oxy}quinolin-2- 19.8 Hz, 0.7H), 4.46 (s, 0.4H), 4.75 (s, yl)methanone0.6H), 7.39 (d, J = 8.7 Hz, 1H), 7.57-7.75 (m, 2H), 7.87 (d, J = 2.6 Hz,1H), 8.10 (dd, J = 12.3, 9.2 Hz, 1H), 8.30 (dd, J = 8.7, 2.4 Hz, 1H),8.46 (t, J = 8.3 Hz, 1H), 8.59 (s, 1H) Example {6-[(5- ¹H NMR (300 MHz,DMSO-d₆) δ ppm MS 244 fluoropyrimidin-2- 8.95 (br s, 2H), 8.79 (s, 2H),8.51 (d, J = 8.6 Hz, 1H), (ESI) yl)oxy]quinolin-2- 8.12 (d, J = 9.2 Hz,1H), 7.89-7.93 (m, 1H), m/z yl}(piperazin-1- 7.91 (d, J = 2.8 Hz, 1H),7.79 (d, J = 8.5 Hz, 1H), 354.2 yl)methanone 7.75 (dd, J = 9.2, 2.8 Hz,1H), 3.91-3.94 (m, [M + H]⁺ 2H), 3.79-3.82 (m, 2H), 3.28-3.31 (m, 2H),3.17-3.20 (m, 2H). Example piperazin-1-yl(6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm MS 245 (trifluoromethyl)pyrazin- 8.97 (br s, 2H), 8.86(s, 1H), 8.75 (s, 1H), 8.54 (d, (ESI) 2- J = 8.5 Hz, 1H), 8.15 (d, J =9.2 Hz, 1H), 8.00 (d, m/z yl]oxy}quinolin-2- J = 2.8 Hz, 1H), 7.80-7.84(m, 2H), 404.1 yl)methanone 3.91-3.93 (m, 2H), 3.79-3.81 (m, 2H),3.28-3.31 (m, 2H), [M + H]⁺ 3.17-3.20 (m, 2H). Examplepiperazin-1-yl(6-{[6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.50 (d, MS 246(trifluoromethyl)pyridazin- J = 8.5 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H),8.15 (d, (ESI) 3- J = 9.2 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.89 (d,m/z yl]oxy}quinolin-2- J = 9.2 Hz, 1H), 7.81 (dd, J = 9.2, 2.8 Hz, 1H),404.1 yl)methanone 7.70 (d, J = 8.5 Hz, 1H), 3.63-3.66 (m, 2H), [M + H]⁺3.35-3.37 (m, 2H), 2.80-2.82 (m, 2H), 2.67-2.70 (m, 2H), 1.90 (s, 3H)Example piperazin-1-yl(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.15 (s,MS 247 (trifluoromethyl)pyrimidin- 2H), 8.94 (br s, 2H), 8.54 (d, J =8.5 Hz, 1H), (ESI) 2- 8.15 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.4 Hz,1H), m/z yl]oxy}quinolin-2- 7.79-7.83 (m, 2H), 3.91-3.94 (m, 2H), 404.1yl)methanone 3.79-3.81 (m, 2H), 3.28-3.31 (m, 2H), 3.17-3.20 (m, [M +H]⁺ 2H). Example [(3aR,4S,6aS)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCIm/z 248 aminohexahydrocyclopenta[c]pyrrol- 1.13-1.53 (m, 2H), 1.71-2.14(m, 3H), 443.0 2(1H)-yl](6-{[5- 2.18-2.37 (m, 1H), 2.76 (qd, J = 8.5,4.3 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 2.90 (dd, J = 12.8, 6.1Hz, 1H), 3.04 (dd, J = 11.9, 2- 5.9 Hz, 1H), 3.41-3.52 (m, 1H),yl]oxy}quinolin-2- 3.53-3.77 (m, 2H), 3.85 (td, J = 11.5, 8.1 Hz, 1H),yl)methanone 7.39 (d, J = 8.8 Hz, 1H), 7.66-7.74 (m, 1H), 7.80 (dd, J =8.5, 1.8 Hz, 1H), 7.89 (t, J = 2.6 Hz, 1H), 8.13 (dd, J = 9.1, 5.8 Hz,1H), 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.46 (dd, J = 8.5, 2.9 Hz, 1H),8.59 (s, 1H) Example piperazin-1-yl{6-[4- ¹H NMR (400 MHz, DMSO-d₆) δppm DCI m/z 249 (trifluoromethyl)phenoxy]quinolin- 2.50 (m, 2H),2.62-2.75 (m, 2H), 2.75-2.88 (m, 402.0 2- 2H), 3.54-3.71 (m, 2H), 7.30(d, J = 8.6 Hz, [M + H]⁺ yl}methanone 2H), 7.53-7.73 (m, 3H), 7.80 (d, J= 8.7 Hz, 2H), 8.04-8.20 (m, 1H), 8.36-8.54 (m, 1H) Example(6-{[3-fluoro-5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 250(trifluoromethyl)pyridin- 9.02 (br s, 2H), 8.50-8.54 (m, 2H), 8.41 (s,1H), (ESI) 2- 8.15 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), m/zyl]oxy}quinolin-2- 7.80-7.83 (m, 2H), 3.92-3.94 (m, 2H), 421.1yl)(piperazin-1- 3.80-3.82 (m, 2H), 3.28-3.31 (m, 2H), 3.17-3.20 (m,[M + H]⁺ yl)methanone 2H). Example N-[2- ¹H NMR (400 MHz, DMSO-d₆) δ ppmESI m/z 251 (methylsulfonyl)ethyl]- 9.22-9.15 (m, 1H), 8.63-8.52 (m,2H), 440.1 6-{[5- 8.35-8.28 (m, 1H), 8.22-8.15 (m, 2H), 7.94 (d, J = 2.6Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.77 (dd, J = 9.1, 2.6 Hz,1H), 2- 7.44-7.38 (m, 1H), 3.86-3.77 (m, 2H), yl]oxy}quinoline-2-3.54-3.40 (m, 2H), 3.07 (s, 3H). carboxamide Example [4-(oxetan-3- ¹HNMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 252 yl)piperazin-1-yl](6- 8.59 (dd,J = 2.5, 1.3 Hz, 1H), 8.48 (d, J = 8.4 Hz, 459.1 {[5- 1H), 8.30 (dd, J =8.7, 2.6 Hz, 1H), 8.10 (d, J = 9.0 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 7.89 (d, J = 2.6 Hz, 1H), 2- 7.74-7.67(m, 2H), 7.39 (d, J = 8.6 Hz, 1H), 4.55 (t, yl]oxy}quinolin-2- J = 6.5Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), yl)methanone 3.75 (d, J = 4.6 Hz,2H), 3.56-3.42 (m, 3H), 2.40 (t, J = 4.8 Hz, 2H), 2.29 (t, J = 4.7 Hz,2H). Example 3,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 253dihydroisoquinolin- 8.62-8.57 (m, 1H), 8.51 (d, J = 8.1 Hz, 1H), 450.12(1H)-yl(6-{[5- 8.31 (dd, J = 8.7, 2.7 Hz, 1H), 8.13 (dd, J = 9.1, 2.5Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.91 (d, J = 2.6 Hz, 1H), 2-7.79-7.70 (m, 2H), 7.44-7.37 (m, 1H), 7.33-7.15 (m, yl]oxy}quinolin-2-4H), 4.88 and 4.73 (2s, 2H), 3.94 and 3.71 (2t, yl)methanone J = 5.8 Hz,2H), 3.00-2.90 (m, 2H). Example [4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESIm/z 254 (methylsulfonyl)piperidin- 8.61-8.57 (m, 1H), 8.49 (d, J = 8.4Hz, 1H), 480.1 1-yl](6-{[5- 8.30 (dd, J = 8.6, 2.6 Hz, 1H), 8.12 (d, J =9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.90 (d, J = 2.6 Hz,1H), 7.73 (t, J = 1.3 Hz, 2- 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.39 (d, J =8.6 Hz, yl]oxy}quinolin-2- 1H), 4.70 (m, 1H), 3.93 (m, 1H), yl)methanone3.45 (m, 1H), 3.18 (m, 1H), 2.97 (s, 3H), 2.93 (m, 1H), 2.20 (m, 1H),2.01 (m, 1H), 1.75-1.62 (m, 2H). Example (4-hydroxy-4- ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.59 (d, ESI m/z 255 methylpiperidin-1- J = 2.5 Hz, 1H),8.46 (d, J = 8.4 Hz, 1H), 432.0 yl)(6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz,1H), 8.10 (d, J = 9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.88(d, J = 2.6 Hz, 1H), 7.70 (dd, J = 9.0, 2- 2.6 Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.39 (d, yl]oxy}quinolin-2- J = 8.6 Hz, 1H), 4.46 (s, 1H),4.20-4.12 (m, yl)methanone 1H), 3.43-3.23 (m, 3H), 2.67 (s, 3H),1.63-1.41 (m, 4H). Example (4-hydroxypiperidin- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 256 1-yl)(6-{[5- 8.61-8.56 (m, 1H), 8.47 (d, J =8.4 Hz, 1H), 418.1 (trifluoromethyl)pyridin- 8.30 (dd, J = 8.7, 2.6 Hz,1H), 8.10 (d, J = 9.0 Hz, [M + H]⁺ 2- 1H), 7.88 (d, J = 2.6 Hz, 1H),7.73-7.64 (m, yl]oxy}quinolin-2- 2H), 7.39 (d, J = 8.6 Hz, 1H), 4.80 (d,J = 4.0 Hz, yl)methanone 1H), 4.14-3.98 (m, 1H), 3.78 (dq, J = 8.1, 4.1Hz, 1H), 3.64-3.54 (m, 1H), 3.24-3.13 (m, 1H), 1.91-1.81 (m, 1H),1.79-1.69 (m, 1H), 1.52-1.35 (m, 2H). Example [(1R,4R,6R)-6- ¹H NMR (400MHz, DMSO-d₆, rotamers) δ MS 257 (hydroxymethyl)-2- ppm 8.62-8.56 (m,1H), 8.48-8.42 (m, 1H), (ESI) azabicyclo[2.2.1]hept- 8.30 (dd, J = 8.7,2.5 Hz, 1H), 8.22 (d, J = 9.1 Hz, m/z 2-yl](6-{[5- 0.7H), 8.13 (d, J =9.1 Hz, 0.3H), 7.88 (dd, 444.1 (trifluoromethyl)pyridin- J = 5.4, 2.8Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), [M + H]⁺ 2- 7.74-7.66 (m, 1H), 7.39(d, J = 8.7 Hz, 1H), yl]oxy}quinolin-2- 4.70-4.63 (m, 1.3H), 4.54 (t, J= 5.5 Hz, yl)methanone 0.7H), 3.80-3.71 (m, 0.3H), 3.49-3.43 (m, 0.7H),3.26-3.10 (m, 3H), 2.61-2.53 (m, 1H), 2.42-2.29 (m, 0.7H), 2.14-2.04 (m,0.3H), 1.64-1.49 (m, 2H), 1.31-1.22 (m, 2H). Example [(1R,4R,6S)-6- ¹HNMR (400 MHz, DMSO-d₆, rotamers) δ MS 258 (hydroxymethyl)-2- ppm8.61-8.58 (m, 1H), 8.51 (d, J = 8.6 Hz, (ESI) azabicyclo[2.2.1]hept-0.7H), 8.48 (d, J = 8.6 Hz, 0.3H), 8.31 (dd, J = 8.7, m/z 2-yl](6-{[5-2.3 Hz, 1H), 8.14 (d, J = 9.1 Hz, 0.3H), 444.1 (trifluoromethyl)pyridin-8.08 (d, J = 9.1 Hz, 0.7H), 7.93-7.88 (m, [M + H]⁺ 2- 1.3H), 7.86 (d, J= 8.5 Hz, 0.7H), 7.75 (dd, J = 9.1, yl]oxy}quinolin-2- 2.7 Hz, 0.7H),7.71 (dd, J = 9.1, 2.7 Hz, yl)methanone 0.3H), 7.40 (dd, J = 8.7, 3.5Hz, 1H), 5.30 (dd, J = 7.6, 4.2 Hz, 0.7H), 4.81 (s, 0.7H), 4.69 (s,0.3H), 4.28 (dd, J = 7.3, 4.9 Hz, 0.3H), 3.89-3.81 (m, 0.3H), 3.59-3.50(m, 0.7H), 3.44-3.33 (m, 2H), 3.01 (d, J = 12.0 Hz, 1H), 2.60-2.53 (m,1H), 2.34-2.13 (m, 1H), 1.86-1.75 (m, 1H), 1.75-1.60 (m, 1H), 1.57 (d, J= 9.6 Hz, 1H), 0.97-0.84 (m, 1H). Example N-[(3aR,4R,6aS)-2- ¹H NMR (400MHz, DMSO-d₆, rotamers) δ DCI m/z 259benzyloctahydrocyclopenta[c]pyrrol- ppm 1.32-1.47 (m, 1.4H), 1.61-2.06(m, 533.0 4-yl]- 3.6H), 2.11-2.31 (m, 2H), 2.54-2.87 (m, [M + H]⁺ 6-{[5-3H), 3.44-3.67 (m, 1H), 3.67-3.85 (m, 1H), (trifluoromethyl)pyridin-4.23-4.60 (m, 1H), 7.04-7.21 (m, 3H), 2- 7.35-7.49 (m, 3H), 7.62-7.71(m, 1H), yl]oxy}quinoline-2- 7.87-7.99 (m, 1H), 8.05 (d, J = 9.2 Hz,1H), carboxamide 8.11-8.25 (m, 1H), 8.25-8.37 (m, 1H), 8.55 (ddd, J =15.5, 6.5, 1.8 Hz, 2H), 9.04-9.18 (m, 1H) Example (4-methyl-1,4- ¹H NMR(400 MHz, DMSO-d₆) δ ppm DCI m/z 260 diazepan-1-yl)(6-{[5- 1.79 (dt, J =11.4, 5.9 Hz, 1H), 1.84-2.02 (m, 1H), 431.0 (trifluoromethyl)pyridin-2.28 (dd, J = 25.6, 6.9 Hz, 3H), 2.53-2.63 (m, [M + H]⁺ 2- 3H),2.65-2.76 (m, 1H), 3.41-3.57 (m, 2H), yl]oxy}quinolin-2- 3.71 (ddd, J =12.4, 7.4, 4.7 Hz, 2H), 7.39 (dd, yl)methanone J = 8.6, 0.6 Hz, 1H),7.61-7.77 (m, 2H), 7.88 (d, J = 2.6 Hz, 1H), 8.00-8.18 (m, 1H), 8.30(dd, J = 8.7, 2.6 Hz, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.54-8.67 (m, 1H)Example (4- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS 261 cyclopropylpiperazin-8.58-8.59 (m, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.30 (dd, (ESI)1-yl)(6-{[5- J = 8.7, 2.6 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.89 (d, J = 2.8 Hz, 1H), 7.68-7.72 (m, 2H),443.1 2- 7.39 (d, J = 8.5 Hz, 3.66-3.68 (m, 2H), 1H), [M + H]⁺yl]oxy}quinolin-2- 3.40-3.42 (m, 2H), 2.64-2.67 (m, 2H), yl)methanone2.53-2.56 (m, 2H), 1.67-1.72 (m, 1H), 0.42-0.46 (m, 2H), 0.32-0.36 (m,2H). Example (4-phenylpiperazin-1- (500 MHz, DMSO-d₆) δ ppm 8.50 (d, J =8.5 Hz, MS 262 yl)(6-{[5- 1H), 8.60 (s, 1H). 8.51 (dd, J = 8.7, 2.6 Hz,(ESI) (trifluoromethyl)pyridin- 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.91 (d,J = 2.8 Hz, m/z 2- 1H), 7.71-7.76 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H),479.1 yl]oxy}quinolin-2- 7.39-7.41 (m, 2H), 6.97-6.98 (m, 2H), 6.82 (t,[M + H]⁺ yl)methanone J = 7.3 Hz, 1H), 3.86-3.88 (m, 2H), 3.64-3.66 (m,2H), 3.28-3.30 (m, 2H), 3.16-3.18 (m, 2H). Example [(3R)-3- ¹H NMR (500MHz, DMSO-d₆ rotamers) δ DCI m/z 263 isopropylpiperazin-1- ppm 0.77 (dd,J = 63.1, 6.8 Hz, 3H), 0.97 (d, J = 6.6 Hz, 445.0 yl](6-{[5- 3H), 1.56(ddq, J = 87.5, 13.4, 6.7 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H),2.14-2.47 (m, 2H), 2.54-2.90 (m, 2- 3H), 2.97-3.15 (m, 1H), 3.56 (d, J =13.0 Hz, yl]oxy}quinolin-2- 0.5H), 3.82 (d, J = 12.3 Hz, 0.5H), 4.43(dd, J = 42.0, yl)methanone 12.5 Hz, 1H), 7.40 (dd, J = 8.7, 4.4 Hz,1H), 7.70 (ddd, J = 16.8, 10.8, 5.5 Hz, 2H), 7.89 (t, J = 2.6 Hz, 1H),8.10 (dd, J = 9.1, 4.0 Hz, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.47 (dd, J =8.5, 2.6 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H) Example N-(piperidin-4-yl)-6-¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 264 {[5- 8.61-8.60 (m, 2H), 8.53 (d,J = 8.5 Hz, 1H), (ESI) (trifluoromethyl)pyridin- 8.31 (dd, J = 8.7, 2.6Hz, 1H), 8.23 (d, J = 9.1 Hz, m/z 2- 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.92(d, J = 2.6 Hz, 417.1 yl]oxy}quinoline-2- 1H), 7.75 (dd, J = 9.1, 2.6Hz, 1H), [M + H]⁺. carboxamide 7.40 (d, J = 8.7 Hz, 1H), 3.95-3.84 (m,1H), 3.02-2.94 (m, 2H), 2.58-2.50 (m, 2H), 2.17-1.85 (br s, 1H)1.83-1.75 (m, 2H), 1.59-1.50 (m, 2H) Example [4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 265 (hydroxymethyl)piperidin- 8.61-8.56 (m, 1H),8.47 (d, J = 8.4 Hz, 1H), 432.2 1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz,1H), 8.10 (d, J = 9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.88(d, J = 2.6 Hz, 1H), 7.73-7.62 (m, 2- 2H), 7.39 (d, J = 8.6 Hz, 1H),4.60-4.47 (m, yl]oxy}quinolin-2- 2H), 3.74-3.65 (m, 1H), 3.17 (m, 1H),yl)methanone 3.06 (t, J = 11.6 Hz, 1H), 2.81 (tt, J = 55.6, 27.7 Hz,1H), 1.91-1.49 (m, 3H), 1.31-1.01 (m, 2H). Example [3- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 266 (hydroxymethyl)pyrrolidin- 8.61-8.56 (m, 1H),8.47 (d, J = 8.4 Hz, 1H), 418.1 1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz,1H), 8.10 (d, J = 9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.88(d, J = 2.6 Hz, 1H), 7.73-7.62 (m, 2- 2H), 7.39 (d, J = 8.6 Hz, 1H),4.75 and yl]oxy}quinolin-2- 4.64 (2m, 1H), 3.85-3.41 (m, 6H), 2.36 (m,1H), yl)methanone 1.99 (m, 1H), 1.70 (m, 1H). Example N-(8- ¹H NMR (400MHz, DMSO-d₆) δ ppm MS 267 azabicyclo[3.2.1]oct- 8.64-8.59 (m, 1H), 8.52(d, J = 8.6 Hz, 1), 8.47 (d, J = 8.6 Hz, (ESI) 3-yl)-6-{[5- 1H), 8.31(dd, J = 8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.21 (d, J =9.2 Hz, 1H) 8.15 (d, J = 8.7 Hz, 443.2 2- 1H), 7.91 (d, J = 2.6 Hz, 1H),7.75 (dd, J = 9.1, [M + H]⁺ yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.40 (d, J= 8.6 Hz, 1H), carboxamide 4.33-4.18 (m, 1H), 3.46 (br s, 2H), 1.85-1.58(m, 8H) Example [4-(pyrazin-2- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS 268yl)piperazin-1-yl](6- 8.59-8.60 (m, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.35(d, (ESI) {[5- J = 1.5 Hz, 1H), 8.31 (dd, J = 9.0, 2.3 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.11-8.15 (m, 2H), 7.91 (d, J = 2.8 Hz, 1H),481.0 2- 7.88 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.40 (d, J = 8.5 Hz,yl)methanone 1H), 3.84-3.87 (m, 2H), 3.75-3.78 (m, 2H), 3.64-3.66 (m,4H). Example [4-(pyridin-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 269yl)piperazin-1-yl](6- 8.59-8.60 (m, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.34(d, (ESI) {[5- J = 2.8 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.03 (dd, J = 4.4, 1.4 Hz, 1H), 7.91 (d, J =2.8 Hz, 480.1 2- 1H), 7.71-7.77 (m, 2H), 7.35-7.41 (m, 2H), [M + H]⁺yl]oxy}quinolin-2- 7.24 (dd, J = 8.5, 4.6 Hz, 1H), 3.36-3.39 (m,yl)methanone 2H), 3.66-3.69 (m, 2H), 3.24-3.27 (m, 2H). Example[4-(pyrimidin-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 270yl)piperazin-1-yl](6- 8.59-8.60 (m, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.40(d, (ESI) {[5- J = 4.9 Hz, 2H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.13 (d, 9.2 Hz, 1H), 7.91 (d, J = 2.4 Hz,1H), 481.1 2- 7.71-7.77 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 6.68 (t, J = 4.7 Hz, 1H), 3.90-3.93 (m, 2H),yl)methanone 3.79-3.82 (m, 4H), 3.58-3.61 (m, 2H). Example[4-(pyridazin-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 271yl)piperazin-1-yl](6- 8.59-8.60 (m, 2H), 8.51 (d, J = 8.5 Hz, 1H), 8.31(dd, (ESI) {[5- J = 8.7, 2.6 Hz, 1H), 8.14 (d, 9.2 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.91 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.5 Hz,1H), 481.2 2- 7.73 (dd, J = 9.2, 2.4 Hz, 1H), 7.39-7.44 (m, 2H), [M +H]⁺ yl]oxy}quinolin-2- 7.27-7.29 (m, 1H), 3.86-3.88 (m, 2H),yl)methanone 3.77-3.80 (m, 2H), 3.66-3.68 (m, 4H). Example[4-(5-chloropyridin- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 2722-yl)piperazin-1- 3.49-3.59 (m, 2H), 3.63 (dd, J = 6.7, 3.2 Hz, 2H),514.0 yl](6-{[5- 3.67 (dd, J = 10.8, 6.4 Hz, 2H), 3.77-3.89 (m, [M + H]⁺(trifluoromethyl)pyridin- 2H), 6.91 (d, J = 9.1 Hz, 1H), 7.40 (d, J =8.7 Hz, 2- 1H), 7.64 (dd, J = 9.1, 2.7 Hz, 1H), yl]oxy}quinolin-2-7.69-7.81 (m, 2H), 7.90 (d, J = 2.6 Hz, 1H), yl)methanone 8.06-8.22 (m,2H), 8.26-8.40 (m, 1H), 8.50 (d, J = 8.5 Hz, 1H), 8.60 (s, 1H) Example[(3S)-3- ¹H NMR (400 MHz, DMSO-d₆ rotamers) δ DCI m/z 273ethylpiperazin-1- ppm 0.74 (t, J = 7.5 Hz, 1.3H), 0.95 (t, J = 7.5 Hz,431.0 yl](6-{[5- 1.7H), 1.08-1.34 (m, 1H), [M + H]⁺(trifluoromethyl)pyridin- 1.34-1.54 (m, 1H), 2.50-2.94 (m, 4H),2.94-3.15 (m, 2- 1H), 3.65 (dd, J = 57.9, 12.5 Hz, 2H), 4.40 (dd,yl]oxy}quinolin-2- J = 26.3, 11.1 Hz, 1H), 7.39 (dt, J = 16.4, 8.2 Hz,yl)methanone 1H), 7.62-7.80 (m, 2H), 7.90 (dd, J = 12.2, 10.7 Hz, 1H),8.10 (dd, J = 9.1, 3.5 Hz, 1H), 8.30 (dd, J = 8.7, 2.4 Hz, 1H), 8.47 (d,J = 8.5 Hz, 1H), 8.53-8.66 (m, 1H) Example [(3S)-3- ¹H NMR (500 MHz,DMSO-d₆ rotamers) δ DCI m/z 274 isopropylpiperazin-1- ppm 0.77 (dd, J =63.1, 6.8 Hz, 3H), 0.97 (d, J = 6.6 Hz, 445.0 yl](6-{[5- 3H), 1.56 (ddq,J = 87.5, 13.4, 6.7 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H),2.14-2.47 (m, 2H), 2.54-2.90 (m, 2- 3H), 2.97-3.15 (m, 1H), 3.56 (d, J =13.0 Hz, yl]oxy}quinolin-2- 0.5H), 3.82 (d, J = 12.3 Hz, 0.5H), 4.43(dd, J = 42.0, yl)methanone 12.5 Hz, 1H), 7.40 (dd, J = 8.7, 4.4 Hz,1H), 7.70 (ddd, J = 16.8, 10.8, 5.5 Hz, 2H), 7.89 (t, J = 2.6 Hz, 1H),8.10 (dd, J = 9.1, 4.0 Hz, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.47 (dd, J =8.5, 2.6 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H) Example {6-[4-(1- ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.35 (t, DCI m/z 275 hydroxyethyl)phenoxy]quinolin-J = 6.6 Hz, 3H), 2.75 (s, 2H), 2.87 (s, 2H), 378.0 2- 3.67 (s, 2H), 4.76(d, J = 6.3 Hz, 1H), 5.19 (s, [M + H]⁺ yl}(piperazin-1- 1H), 7.00-7.22(m, 3H), 7.29-7.47 (m, 4H), yl)methanone 7.50-7.68 (m, 3H), 7.98-8.12(m, 1H), 8.23-8.51 (m, 1H) Example [(3S)-3- ¹H NMR (400 MHz, DMSO-d₆rotamers) δ DCI m/z 276 (hydroxymethyl)piperazin- ppm 2.81 (ddt, J =39.0, 23.3, 11.0 Hz, 4), 433.0 1-yl](6-{[5- 3.02-3.29 (m, 4H), 3.72 (dd,J = 37.2, 12.5 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 4.40 (d, J =12.9 Hz, 0.5H), 4.52 (d, J = 12.8 Hz, 2- 0.5H), 4.68 (s, 0.5H), 4.90 (s,0.5H), yl]oxy}quinolin-2- 7.39 (d, J = 8.8 Hz, 1H), 7.57-7.78 (m, 2H),yl)methanone 7.89 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.31(dd, J = 8.7, 2.4 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.59 (s, 1H)Example isopropyl 4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 277(trifluoromethyl)pyridin- 8.59-8.60 (m, 1H). 8.49 (d, J = 8.2 Hz, 8.31(dd, (ESI) 2- J = 8.7, 2.6 Hz, 1H), 1H), 8.12 (d, J = 9.2 Hz, m/zyl]oxy}quinolin-2- 1H), 7.90 (d, J = 2.4 Hz, 7.71-7.75 (m, 2H), 489.1yl)carbonyl]piperazine- 1H), 7.40 (d, J = 8.5 Hz, 1H), 3.70-3.73 (m,[M + H]⁺ 1-carboxylate 2H), 3.51-3.52 (m, 4H), 3.42-3.44 (m, 2H), 1.20(d, J = 6.4 Hz, 6H). Example (1S,5S)-3,6- ¹H NMR (400 MHz, DMSO-d₆,rotamers) δ MS 278 diazabicyclo[3.2.0]hept- ppm 8.59 (s, 1H), 8.49 (dd,J = 8.5, 4.5 Hz, (ESI) 3-yl(6-{[5- 1H), 8.30 (dd, J = 8.7, 2.4 Hz, 1H),8.13 (dd, J = 9.1, m/z (trifluoromethyl)pyridin- 3.0 Hz, 1H), 7.92-7.84(m, 2H), 415.1 2- 7.74-7.68 (m, 1H), 7.39 (d, J = 8.7 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 4.37 (dd, J = 11.4, 5.1 Hz, 1H), 4.23 (d, J = 13.0Hz, yl)methanone 0.5H), 4.10 (d, J = 13.1 Hz, 0.5H), 4.00 (d, J = 12.4Hz, 0.5H), 3.84 (d, J = 12.6 Hz, 0.5H), 3.74-3.65 (m, 1H), 3.65-3.55 (m,1H), 3.44 (dd, J = 13.0, 7.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.22-3.12 (m,1H), 3.11-3.03 (m, 1H). Example 1,6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS279 diazaspiro[3.3]hept- 8.62-8.57 (m, 1H), 8.53-8.48 (m, 1H), 8.31 (dd,J = 8.7, (ESI) 1-yl(6-{[5- 2.4 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.09-8.02 (m, 1H), 7.91-7.88 (m, 1H), 415.1 2-7.76-7.70 (m, 1H), 7.40 (d, J = 8.7 Hz, 1H), [M + H]⁺ yl]oxy}quinolin-2-4.68-4.54 (m, 3H), 3.73 (d, J = 9.7 Hz, 2H), yl)methanone 3.53-3.46 (m,2H), 2.66-2.56 (m, 2H). Example (3aS,6aS)- ¹H NMR (400 MHz, DMSO-d₆) δppm MS 280 hexahydropyrrolo[3,4- 8.60-8.56 (m, 1H), 8.46 (d, J = 8.5 Hz,1H), (ESI) b]pyrrol-5(1H)-yl(6- 8.30 (dd, J = 8.7, 2.6 Hz, 1H),8.15-8.09 (m, 1H), m/z {[5- 7.88 (d, J = 2.6 Hz, 1H), 7.84-7.77 (m, 1H),429.2 (trifluoromethyl)pyridin- 7.74-7.68 (m, 1H), 7.39 (d, J = 8.6 Hz,1H), [M + H]⁺ 2- 3.96-3.68 (m, 3H), 3.62-3.53 (m, 1H),yl]oxy}quinolin-2- 3.51-3.40 (m, 1H), 2.96-2.86 (m, 1H), yl)methanone2.86-2.69 (m, 2H), 1.92-1.73 (m, 1H), 1.68-1.48 (m, 1H). ExampleN-(morpholin-4-yl)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.90 (s, ESI m/z 2816-{[5- 1H), 8.64-8.59 (m, 1H), 8.52 (d, J = 8.5 Hz, 419.1(trifluoromethyl)pyridin- 1H), 8.32 (dd, J = 8.6, 2.7 Hz, 1H), 8.22 (d,J = 9.1 Hz, [M + H]⁺ 2- 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.92 (d,yl]oxy}quinoline-2- J = 2.6 Hz, 1H), 7.79-7.72 (m, 1H), 7.41 (d, J = 8.6Hz, carboxamide 1H), 3.75-3.64 (m, 4H), 3.02-2.89 (m, 4H). Example[(3R)-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (s, ESI m/z 282hydroxypyrrolidin-1- 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.31 (m, 1H), 404.1yl](6-{[5- 8.14 (m, 1H), 7.88-7.84 (m, 2H), 7.71 (m, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.41 (m, 1H), 4.97 (m, 1H), 4.34 (m, 1H), 2-3.85-3.62 (m, 4H), 2.01-1.83 (m, 2H). yl]oxy}quinolin-2- yl)methanoneExample [(3S)-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, ESI m/z 283hydroxypyrrolidin-1- J = 3.0 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 404.1yl](6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.14 (dd, J = 9.1, 6.8 Hz,[M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.92-7.82 (m, 2H), 7.72 (ddd, J= 9.0, 2- 2.7, 1.3 Hz, 1H), 7.43-7.37 (m, 1H), yl]oxy}quinolin-2- 5.00(dd, J = 31.4, 3.4 Hz, 1H), 4.40-4.28 (m, yl)methanone 1H), 3.91-3.76(m, 2H), 3.71-3.56 (m, 2H), 2.01-1.80 (m, 2H). Example(4-hydroxyazepan-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (s, ESI m/z 284yl)(6-{[5- 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.30 (dd, J = 8.7, 432.1(trifluoromethyl)pyridin- 2.5 Hz, 1H), 8.09 (dd, J = 9.1, 3.1 Hz, 1H),[M + H]⁺ 2- 7.88 (t, J = 2.3 Hz, 1H), 7.76-7.59 (m, 2H),yl]oxy}quinolin-2- 7.74-7.62 (m, 2H), 7.39 (d, J = 8.8 Hz, 1H),yl)methanone 4.58 (dd, J = 18.3, 3.9 Hz, 1H), 3.76 (s, 1H), 3.72-3.49(m, 2H), 3.44 (d, J = 13.9 Hz, 1H), 1.97 (d, J = 11.7 Hz, 2H), 1.87-1.53(m, 5H). Example N-(4-hydroxy-1,1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.88(d, ESI m/z 285 dioxidotetrahydrothiophen- J = 8.1 Hz, 1H), 8.62 (d, J =2.4 Hz, 1H), 468.0 3-yl)-6-{[5- 8.58 (d, J = 8.5 Hz, 1H), 8.32 (dd, J =8.7, 2.6 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.25-8.18 (m, 2H),7.95 (d, J = 2.6 Hz, 2- 1H), 7.78 (dd, J = 9.1, 2.6 Hz, 1H), 7.41 (d, J= 8.6 Hz, yl]oxy}quinoline-2- 1H), 6.30 (s, 1H), 4.80 (dtd, J = 11.5,carboxamide 7.7, 3.7 Hz, 1H), 4.66-4.61 (m, 1H), 3.63-3.37 (m, 4H).Example {4-[(3-methyloxetan- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 2863- 8.61-8.56 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H), 487.2yl)methyl]piperazin- 8.34-8.27 (m, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.89(d, [M + H]⁺ 1-yl}(6-{[5- J = 2.6 Hz, 1H), 7.74-7.66 (m, 2H), 7.39 (d, J= 8.6 Hz, (trifluoromethyl)pyridin- 1H), 4.36 (d, J = 5.5 Hz, 2H), 2-4.21-4.13 (m, 2H), 3.69 (t, J = 4.6 Hz, 2H), yl]oxy}quinolin-2-3.47-3.41 (m, 2H), 3.34 (m, 2H), 2.43-2.37 (m, yl)methanone 2H), 2.28(t, J = 4.7 Hz, 2H), 1.33 (s, 3H). Example [3- ¹H NMR (400 MHz, DMSO-d₆)δ ppm ESI m/z 287 (methylsulfonyl)pyrrolidin- 8.62-8.57 (m, 1H), 8.50(dd, J = 8.6, 4.6 Hz, 1H), 466.1 1-yl](6-{[5- 8.31 (dd, J = 8.6, 2.6 Hz,1H), 8.16 (t, J = 9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H),7.93-7.86 (m, 2H), 7.73 (ddd, J = 9.0, 2- 3.9, 2.6 Hz, 1H), 7.43-7.37(m, 1H), yl]oxy}quinolin-2- 4.27-4.14 (m, 1H), 4.08-3.92 (m, 2H),yl)methanone 3.86-3.65 (m, 2H), 3.11 and 3.03 (2s, 3H), 2.41-2.29 (m,2H). Example 2-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆ rotamers) δ DCI m/z 288(trifluoromethyl)pyridin- ppm 1.38-1.55 (m, 0.5H), 1.60-1.80 (m, 457.02- 0.5H), 1.96-2.09 (m, 0.5H), 2.12-2.38 (m, [M + H]⁺ yl]oxy}quinolin-2-2.5H), 2.61-3.15 (m, 3H), 3.52-3.75 (m, yl)carbonyl]hexahydropyrrolo[1,1H), 3.84 (dd, J = 30.3, 12.3 Hz, 1H), 3.99 (t, J = 11.7 Hz, 2- 1H),4.60 (d, J = 12.1 Hz, 0.5H), a]pyrazin-6(2H)-one 4.70 (d, J = 12.1 Hz,0.5H), 7.40 (d, J = 8.7 Hz, 1H), 7.62-7.81 (m, 2H), 7.90 (d, J = 2.6 Hz,1H), 8.13 (d, J = 9.1 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.50 (d,J = 8.3 Hz, 1H), 8.59 (s, 1H) Example ethyl 4-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm MS 289 (trifluoromethyl)pyridin- 8.59-8.60 (m, 1H), 8.50(d, J = 8.5 Hz, 1H), 8.31 (dd, (ESI) 2- J = 8.7, 2.6 Hz, 1H), 8.12 (d, J= 9.2 Hz, 1H), m/z yl]oxy}quinolin-2- 7.90 (d, J = 2.4 Hz, 1H),7.71-7.75 (m, 2H), 475.1 yl)carbonyl]piperazine- 7.40 (d, J = 8.9 Hz,1H), 4.07 (q, J = 7.0 Hz, 2H), [M + H]⁺ 1-carboxylate 3.71-3.74 (m, 4H),3.51-3.55 (m, 4H), 3.42-3.44 (m, 2H), 1.20 (t, J = 7.0 Hz, 3H). Examplecyclopropyl{4-[(6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 290 {[5- 8.59-8.60(m, 1H), 8.50 (d, J = 8.5 Hz, 8.31 (dd, (ESI) (trifluoromethyl)pyridin-J = 8.7, 2.6 Hz, 1H), 1H), 8.12 (d, J = 9.2 Hz, m/z 2- 1H), 7.90 (d, J =2.4 Hz, 7.71-7.76 (m, 2H), 471.1 yl]oxy}quinolin-2- 1H), 7.40 (d, J =8.9 Hz, 1H), 3.52-3.85 (m, [M + H]⁺ yl)carbonyl]piperazin- 8H),1.94-2.04 (m, 1H), 0.73-0.78 (m, 4H). 1-yl}methanone Example (4- ¹H NMR(500 MHz, DMSO-d₆) δ ppm MS 291 cyclohexylpiperazin- 8.58-8.59 (m, 1H),8.48 (d, J = 8.5 Hz, 1H), 8.30 (dd, (ESI) 1-yl)(6-{[5- J = 8.7, 2.6 Hz,1H), 8.11 (d, J = 9.2 Hz, 1H), m/z (trifluoromethyl)pyridin- 7.89 (d, J= 2.8 Hz, 1H), 7.68-7.72 (m, 2H), 485.1 2- 7.39 (d, J = 8.5 Hz, 1H),3.66-3.68 (m, 2H), [M + H]⁺ yl]oxy}quinolin-2- 3.40-3.42 (m, 2H),2.64-2.67 (m, 2H), yl)methanone 2.53-2.56 (m, 2H), 1.67-1.72 (m, 1H),0.42-0.46 (m, 2H), 0.32-0.36 (m, 2H). Example (3-fluoro-4- ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.60 (s, ESI m/z 292 hydroxypyrrolidin-1- 1H), 8.50(d, J = 8.7 Hz, 1H), 8.31 (dd, J = 8.7, 422.1 yl)(6-{[5- 2.5 Hz, 1H),8.17 (dd, J = 9.1, 5.0 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin-7.97-7.86 (m, 1H), 7.74 (dd, J = 9.3, 2.6 Hz, 2- 1H), 7.40 (d, J = 8.7Hz, 1H), 5.67 and yl]oxy}quinolin-2- 5.58 (2br s, 1H), 5.10 and 4.99(2d, J = 7.9 Hz, 1H), yl)methanone 4.30-3.66 (m, 5H). Example isobutyl4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 293(trifluoromethyl)pyridin- 8.59-8.60 (m, 1H). 8.50 (d, J = 8.2 Hz, 1H),8.31 (dd, (ESI) 2- J = 8.6, 2.4 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), m/zyl]oxy}quinolin-2- 7.90 (d, J = 2.4 Hz, 1H), 7.71-7.75 (m, 2H), 503.1yl)carbonyl]piperazine- 7.40 (d, J = 8.9 Hz, 1H), 3.82 (d, J = 6.7 Hz,2H), [M + H]⁺ 1-carboxylate 3.72-3.74 (m, 2H), 3.51-3.54 (m, 4H),3.43-3.45 (m, 2H), 1.85-1.91 (m, 1H), 0.90 (d, J = 6.1 Hz, 6H). Example(4-ethylpiperazin-1- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS 294 yl)(6-{[5-8.58-8.59 (m, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.30 (dd, (ESI)(trifluoromethyl)pyridin- J = 8.7, 2.6 Hz, 1H), 8.11 (d, J = 9.2 Hz,1H), m/z 2- 7.89 (d, J = 2.4 Hz, 1H), 7.68-7.72(m, 2H), 431.1yl]oxy}quinolin-2- 7.39 (d, J = 8.9 Hz, 1H), 3.70-3.73 (m, 2H), [M + H]⁺yl)methanone 3.44-3.47 (m, 2H), 2.47-2.49 (m, 2H), 2.35-2.38 (m, 4H),1.87 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H). Example (6-{[3-bromo-5- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.73 (d, MS 295 (trifluoromethyl)pyridin- J =2.1 Hz, 1H), 8.56-8.52 (m, 1H), 8.48 (d, J = 8.5 Hz, (ESI) 2- 1H), 8.11(d, J = 9.1 Hz, 1H), m/z yl]oxy}quinolin-2- 7.92 (d, J = 2.6 Hz, 1H),7.74 (dd, J = 9.1, 2.6 Hz, 481.0 yl)(piperazin-1- 1H), 7.70 (d, J = 8.5Hz, 1H), 3.69-3.63 (m, [M + H]⁺ yl)methanone 2H), 3.42-3.37 (m, 2H),2.88-2.82 (m, 2H), 2.76-2.68 (m, 2H). Example morpholin-4-yl(6- ¹H NMR(500 MHz, DMSO-d₆) δ ppm MS 296 {[5- 8.58-8.59 (m, 1H). 8.49 (d, J = 8.5Hz, 1H), 8.30 (dd, (ESI) (trifluoromethyl)pyridin- J = 8.9, 2.4 Hz, 1H),8.11 (d, J = 9.2 Hz, 1H), m/z 2- 7.89 (d, J = 2.4 Hz, 1H), 7.70-7.74 (m,2H), 404.1 yl]oxy}quinolin-2- 7.39 (d, J = 8.5 Hz, 1H), 3.71-3.73 (m,4H), [M + H]⁺ yl)methanone 3.59-3.61 (m, 2H), 3.51-3.53 (m, 2H). Examplepiperidin-1-yl(6-{[5- ¹ H NMR (500 MHz, DMSO-d₆) δ ppm MS 297(trifluoromethyl)pyridin- 8.58-8.59 (m, 1H), 8.47 (d, J = 8.5 Hz, 1H),8.30 (dd, (ESI) 2- J = 8.7, 2.6 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), m/zyl]oxy}quinolin-2- 7.88 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 9.0, 2.6 Hz,402.2 yl)methanone 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 8.5 Hz,[M + H]⁺ 1H), 3.66-3.69 (m, 2H), 3.36-3.37 (m, 2H), 1.62-1.66 (m, 4H),1.50-1.53 (m, 1H). Example [4-(2,2- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS298 difluoroethyl)piperazin- 8.59-8.60 (m, 1H), 8.48 (d, J = 8.2 Hz,1H), 8.30 (dd, (ESI) 1-yl](6-{[5- J = 8.5, 2.1 Hz, 1H), 8.11 (d, J = 9.2Hz, 1H), m/z (trifluoromethyl)pyridin- 7.89 (d, J = 2.8 Hz, 1H),7.69-7.73 (m, 2H), 467.1 2- 7.39 (d, J = 8.5 Hz, 1H), 6.17 (tt, J =55.7, 4.3 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 3.71-3.73 (m, 2H),3.47-3.49 (m, 2H), yl)methanone 2.81 (td, J = 15.7, 4.3 Hz, 2H),2.66-2.69 (m, 2H), 2.55-2.57 (m, 2H). Example morpholin-4-yl{4- ¹ H NMR(400 MHz, DMSO-d₆) δ ppm MS 299 [(6-{[5- 8.58-8.59 (m, 1H), 8.49 (d, J =8.2 Hz, 1H), 8.31 (dd, (ESI) (trifluoromethyl)pyridin- J = 9.2, 2.7 Hz,1H), 8.12 (d, J = 9.2 Hz, 1H), m/z 2- 7.90 (d, J = 2.7 Hz, 1H),7.71-7.74 (m, 2H), 516.0 yl]oxy}quinolin-2- 7.39 (d, J = 8.9 Hz, 1H),3.72-3.75 (m, 2H), [M + H]⁺ yl)carbonyl]piperazin- 3.55-3.58 (m, 4H),3.49-3.52 (m, 2H), 1-yl}methanone 3.31-3.34 (m, 2H), 3.20-3.22 (m, 2H),3.16-3.18 (m, 4H). Example [(2S,4R)-4-hydroxy- ¹H NMR (400 MHz, DMSO-d₆)δ ppm ESI m/z 300 2- 8.62-8.58 (m, 1H), 8.47 (dd, J = 8.5, 3.0 Hz, 1H),434.1 (hydroxymethyl)pyrrolidin- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.13(dd, J = 9.1, [M + H]⁺ 1-yl](6-{[5- 5.9 Hz, 1H), 7.89 (t, J = 2.9 Hz,1H), (trifluoromethyl)pyridin- 7.85 (d, J = 8.5 Hz, 1H), 7.79-7.68 (m,1H), 2- 7.40 (d, J = 8.7 Hz, 1H), 5.03-4.23 (m, 4H), yl]oxy}quinolin-2-3.80-3.49 (m, 3H), 3.25-3.03 (m, 1H), yl)methanone 2.18-1.88 (m, 2H).Example [(3R)-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (d, MS 301fluoropyrrolidin-1- J = 8.5 Hz, 1H), 8.29 (d, J = 2.9 Hz, 1H), (ESI)yl](6-{[5- 8.14 (dd, J = 9.1, 5.0 Hz, 1H), 8.04 (dd, J = 8.9, 2.8 Hz,m/z (trifluoromethoxy)pyridin- 1H), 7.92-7.86 (m, 1H), 7.85 (d, J = 2.6Hz, 422.1 2- 1H), 7.70 (dd, J = 9.3, 2.9 Hz, 1H), [M + H]+yl]oxy}quinolin-2- 7.34 (d, J = 8.9 Hz, 1H), 5.52-5.29 (m, 1H),yl)methanone 4.16-3.56 (m, 4H), 2.30-2.03 (m, 2H). Example N-(trans-3-¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.00 (d, ESI m/z 302 hydroxycyclobutyl)-J = 7.6 Hz, 1H), 8.64-8.59 (m, 1H), 8.52 (d, J = 8.5 Hz, 404.1 6-{[5-1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin-8.23 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2- 1H), 7.92 (d, J = 2.6Hz, 1H), 7.76 (dd, J = 9.1, yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.40 (d, J= 8.6 Hz, 1H), 5.04 (d, carboxamide J = 5.0 Hz, 1H), 4.65-4.52 (m, 1H),4.40-4.30 (m, 1H), 2.44 (m, 2H), 2.26-2.15 (m, 2H). Example [trans-3,4-¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.60 (s, ESI m/z 303dihydroxypyrrolidin- 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.31 (m, 1H), 420.11-yl](6-{[5- 8.13 (m, 1H), 7.92-7.84 (m, 2H), 7.72 (m, [M + H]⁺(trifluoromethyl)pyridin- 1H), 7.39 (m, 1H), 5.24 (d, J = 3.0 Hz, 1H),2- 5.15 (bs, 1H), 4.04-3.97 (m, 3H), yl]oxy}quinolin-2- 3.74-3.58 (m,2H), 3.52 (d, J = 12.8 Hz, 1H). yl)methanone Example [(2R,3S)-3-hydroxy-¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 304 2- 8.62-8.57 (m, 1H), 8.47(d, J = 8.5 Hz, 1H), 434.1 (hydroxymethyl)pyrrolidin- 8.31 (dd, J = 8.7,2.6 Hz, 1H), 8.14 (dd, J = 9.1, 6.4 Hz, [M + H]⁺ 1-yl](6-{[5- 1H),7.92-7.87 (m, 1H), 7.81 (dd, J = 8.5, (trifluoromethyl)pyridin- 3.3 Hz,1H), 7.72 (ddd, J = 9.2, 7.0, 2.4 Hz, 2- 1H), 7.40 (dd, J = 8.7, 2.5 Hz,1H), yl]oxy}quinolin-2- 5.03-4.81 (m, 2H), 4.33-4.26 (m, 1H), 4.10 (m,yl)methanone 1H), 3.90-3.38 (m, 3H), 3.25-3.11 (m, 1H), 2.20-2.04 (m,1H), 1.85-1.72 (m, 1H). Example [trans-3-hydroxy-4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.60 (d, ESI m/z 305 methoxypyrrolidin-1- J = 0.8 Hz,1H), 8.48 (d, J = 8.6 Hz, 1H), 434.1 yl](6-{[5- 8.31 (dd, J = 8.7, 2.5Hz, 1H), 8.16 (dd, J = 9.1, 6.3 Hz, [M + H]⁺ (trifluoromethyl)pyridin-1H), 7.93-7.84 (m, 2H), 7.73 (dd, J = 9.1, 2- 2.6 Hz, 1H), 7.40 (d, J =8.7 Hz, 1H), yl]oxy}quinolin-2- 5.32 (m, 1H), 4.20 (m, 1H), 4.00-3.47(m, 5H), yl)methanone 3.34 and 3.26 (2s, 3H). Example[trans-3-hydroxy-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, ESI m/z 306methylpyrrolidin-1- J = 2.3 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 418.1yl](6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.14 (d, J = 9.1 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 7.96-7.81 (m, 2H), 7.72 (dt, J = 9.1, 2.6Hz, 2- 1H), 7.40 (dd, J = 8.7, 1.2 Hz, 1H), yl]oxy}quinolin-2- 5.15 (dd,J = 25.0, 4.2 Hz, 1H), 4.00-3.77 (m, 3H), yl)methanone 3.59 and 3.40(2m, 1H), 3.37 and 3.22 (2m, 1H), 2.08 (m, 1H), 1.04 and 0.93 (2d, J =6.9 Hz, 3H). Example [cis-3,5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z307 bis(hydroxymethyl)piperidin- 8.63-8.58 (m, 1H), 8.47 (d, J = 8.4 Hz,1H), 462.2 1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.11 (d, J = 9.1Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.89 (d, J = 2.6 Hz, 1H),7.71 (dd, J = 9.0, 2- 2.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.40 (d,yl]oxy}quinolin-2- J = 8.6 Hz, 1H), 4.79-4.58 (m, 2H), 4.40 (t, J = 5.2Hz, yl)methanone 1H), 3.87-3.79 (m, 1H), 3.45-3.38 (m, 1H), 3.28-3.19(m, 1H), 3.07 (m, 1H), 2.72-2.62 (m, 1H), 2.39 (t, J = 12.1 Hz, 1H),1.77-1.69 (m, 2H), 0.96-0.82 (m, 1H). Example [4-(pyridin-2- ¹H NMR (400MHz, DMSO-d₆) δ ppm DCI m/z 308 ylmethyl)piperazin-1- 2.43-2.49 (m, 2H),2.53-2.62 (m, 2H), 494.0 yl](6-{[5- 3.46-3.57 (m, 2H), 3.66 (s, 2H),3.71-3.81 (m, 2H), [M + H]⁺ (trifluoromethyl)pyridin- 7.19-7.32 (m, 1H),7.39 (d, J = 8.7 Hz, 1H), 2- 7.48 (d, J = 7.8 Hz, 1H), 7.64-7.74 (m,2H), yl]oxy}quinolin-2- 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.89 (t, J = 4.9Hz, yl)methanone 1H), 8.10 (d, J = 9.1 Hz, 1H), 8.30 (dd, J = 8.7, 2.6Hz, 1H), 8.49 (dd, J = 9.7, 6.6 Hz, 2H), 8.59 (s, 1H) Example3,3-dimethyl-1-{4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 309 [(6-{[5-8.59-8.60 (m, 1H). 8.50 (d, J = 8.5 Hz, 1H), 8.31 (dd, (ESI)(trifluoromethyl)pyridin- J = 8.5, 2.4 Hz, 1H), 8.12 (d, J = 9.2 Hz,1H), m/z 2- 7.90 (d, J = 2.4 Hz, 1H), 7.71-7.76 (m, 2H), 501.1yl]oxy}quinolin-2- 7.39 (d, J = 8.9 Hz, 1H), 3.64-3.71 (m, 4H), [M + H]⁺yl)carbonyl]piperazin- 3.49-3.56 (m, 4H), 2.27 (s, 2H), 0.99 (s, 9H).1-yl}butan-1-one Example [(3R)-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60(s, MS 310 aminopyrrolidin-1- 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.30 (dd, J= 8.7, (ESI) yl](6-{[5- 2.5 Hz, 1H), 8.13 (dd, J = 9.1, 4.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.89-7.88 (m, 1H), 7.84 (dd, J = 8.5, 2.3 Hz,403.2 2- 1H), 7.71 (ddd, J = 9.1, 2.2, 2.2 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.39 (d, J = 8.7 Hz, 1H), 3.80-3.25 (m, 7H),yl)methanone 2.05-1.93 (m, 1H), 1.72-1.61 (m, 1H) Example (6-{[5- ¹H NMR(400 MHz, DMSO-d₆) δ ppm MS 311 (trifluoromethyl)pyridin- 8.58-8.59 (m,1H). 8.48 (d, J = 8.6 Hz, 1H), 8.30 (dd, (ESI) 2- J = 8.7, 2.6 Hz, 1H),8.11 (d, J = 9.2 Hz, 1H), m/z yl]oxy}quinolin-2- 7.89 (d, J = 2.4 Hz,1H), 7.69-7.73 (m, 2H), 499.1 yl)[4-(3,3,3- 7.39 (d, J = 8.9 Hz, 1H),3.70-3.73 (m, 2H), [M + H]⁺ trifluoropropyl)piperazin- 3.46-3.48 (m,2H), 2.43-2.61 (m, 8H). 1-yl]methanone Example (3,3- ¹H NMR (400 MHz,DMSO-d₆, rotamers) δ DCI m/z 312 difluoropiperidin-1- ppm 1.65-1.85 (m,2H), 2.05-2.25 (m, 2H), 438.0 yl)(6-{[5- 3.47-3.60 (m, 1H), 3.71-3.82(m, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 3.88-4.14 (m, 2H), 7.40 (d,J = 8.7 Hz, 1H), 2- 7.66-7.79 (m, 2H), 7.91 (d, J = 2.1 Hz, 1H), 8.12(d, yl]oxy}quinolin-2- J = 9.1 Hz, 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H),yl)methanone 8.51 (dd, J = 8.5, 4.2 Hz, 1H), 8.59 (s, 1H) Example[(5S,7S)-7-hydroxy- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 3131-azaspiro[4.4]non-1- 1.50-1.68 (m, 2H), 1.69-1.87 (m, 3H), 458.0yl](6-{[5- 1.94-2.28 (m, 3H), 2.40-2.51 (m, 1H), 2.64-2.81 (m, M + H]⁺(trifluoromethyl)pyridin- 1H), 3.55-3.69 (m, 2H), 4.36-4.73 (m, 2H), 2-7.44 (d, J = 8.7 Hz, 1H), 7.71-7.81 (m, 2H), yl]oxy}quinolin-2- 7.93 (t,J = 4.4 Hz, 1H), 8.16 (dd, J = 16.2, yl)methanone 10.5 Hz, 1H),8.30-8.41 (m, 1H), 8.51 (t, J = 9.3 Hz, 1H), 8.66 (t, J = 9.0 Hz, 1H)Example [3-(azetidin-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 314yl)pyrrolidin-1-yl](6- 1.59-2.06 (m, 4H), 2.80-3.09 (m, 3H), 443.0 {[5-3.09-3.19 (m, 2H), 3.36-3.90 (m, 4H), 7.38 (t, J = 13.9 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 7.71 (dt, J = 9.0, 4.5 Hz, 1H), 2-7.79-7.92 (m, 2H), 8.11 (dt, J = 20.0, 10.2 Hz, 1H), yl]oxy}quinolin-2-8.30 (dd, J = 8.8, 2.4 Hz, 1H), 8.47 (dd, J = 8.5, yl)methanone 2.1 Hz,1H), 8.52-8.65 (m, 1H) Example [4-(1,3-oxazol-4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm DCI m/z 315 ylmethyl)piperazin-1- 2.34-2.48 (m, 2H), 2.55(dd, J = 12.0, 7.2 Hz, 2H), 484.0 yl](6-{[5- 3.40-3.55 (m, 4H),3.66-3.83 (m, 2H), [M + H]⁺ (trifluoromethyl)pyridin- 7.39 (d, J = 8.7Hz, 1H), 7.70 (dd, J = 12.9, 5.7 Hz, 2- 2H), 7.89 (d, J = 2.6 Hz, 1H),8.00 (s, 1H), yl]oxy}quinolin-2- 8.06-8.17 (m, 1H), 8.26-8.36 (m, 2H),yl)methanone 8.47 (d, J = 8.6 Hz, 1H), 8.59 (s, 1H) Example[3-(morpholin-4- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCI m/z 316yl)pyrrolidin-1-yl](6- ppm 1.69-1.88 (m, 1H), 2.03-2.22 (m, 1H), 473.0{[5- 2.25-2.49 (m, 4H), 2.74-3.00 (m, 1H), [M + H]⁺(trifluoromethyl)pyridin- 3.45-3.68 (m, 5.4H), 3.89 (m, J = 45.7, 15.3,14.5, 2- 6.2 Hz, 2.7H), 7.39 (d, J = 8.7 Hz, 1H), yl]oxy}quinolin-2-7.71 (dd, J = 9.1, 2.6 Hz, 1H), 7.87 (dd, J = 15.3, yl)methanone 5.6 Hz,2H), 8.14 (dd, J = 9.1, 5.8 Hz, 1H), 8.30 (dd, J = 8.7, 2.6 Hz, 1H),8.47 (d, J = 8.6 Hz, 1H), 8.59 (s, 1H) Example N-(2-sulfamoylethyl)- ¹HNMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 317 6-{[5- 3.31-3.45 (m, 2H), 3.80(dd, J = 13.5, 6.5 Hz, 2H), 441.0 (trifluoromethyl)pyridin- 7.01 (s,2H), 7.40 (t, J = 9.2 Hz, 1H), [M + H]⁺ 2- 7.68-7.84 (m, 1H), 7.94 (d, J= 2.6 Hz, 1H), yl]oxy}quinoline-2- 8.18 (dd, J = 8.8, 6.2 Hz, 2H), 8.55(d, J = 8.6 Hz, carboxamide 1H), 8.63 (d, J = 14.3 Hz, 1H), 9.17 (t, J =6.0 Hz, 1H) Example (4-fluoropiperidin-1- ¹H NMR (400 MHz, DMSO-d₆) δppm DCI m/z 318 yl)(6-{[5- 1.66-2.18 (m, 4H), 3.36-3.49 (m, 1H), 420.0(trifluoromethyl)pyridin- 3.49-3.64 (m, 1H), 3.70-3.84 (m, 2H),4.82-4.96 (m, [M + H]⁺ 2- 1H), 4.96-5.12 (m, 1H), 7.38 (dd, J = 10.9,yl]oxy}quinolin-2- 5.5 Hz, 1H), 7.60-7.77 (m, 2H), 7.88 (dd, J = 7.7,yl)methanone 2.7 Hz, 1H), 8.04-8.17 (m, 1H), 8.25-8.37 (m, 1H),8.42-8.53 (m, 1H), 8.54-8.67 (m, 1H) Example [(3R)-3-(piperidin-1- ¹HNMR (400 MHz, DMSO-d₆) δ ppm MS 319 yl)pyrrolidin-1-yl](6- 8.59-8.60 (m,1H). 8.46 (d, J = 8.6 Hz, 1H), 8.30 (dd, (ESI) {[5- J = 8.7, 2.6 Hz,1H), 8.12-8.15 (m, 1H), 7.89 (d, m/z (trifluoromethyl)pyridin- J = 2.4Hz, 1H), 7.83-7.85 (m, 1H), 471.2 2- 7.70-7.73 (m, 1H), 7.38-7.41 (m,1H), 3.86-3.98 (m, 2H), [M + H]⁺ yl]oxy}quinolin-2- 3.71-3.79 (m, 1H),3.45-3.58 (m, 1H), yl)methanone 3.24-3.29 (m, 1H), 2.77-2.88 (m, 1H),2.39-2.45 (m, 2H), 2.23-2.27 (m, 1H), 2.06-2.17 (m, 1H), 1.68-1.80 (m,1H), 1.34-1.55 (m, 6H). Example piperazin-1-yl(6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.55 (d, MS 320 (trifluoromethyl)- J = 8.2 Hz, 1H), 8.24(d, J = 2.8 Hz, 1H), 8.21 (d, (ESI) 1,3,4-thiadiazol-2- J = 9.2 Hz, 1H),7.95 (dd, J = 9.3, 2.9 Hz, 1H), m/z yl]oxy}quinolin-2- 7.74 (d, J = 8.5Hz, 1H), 3.63-3.65 (m, 2H), 410.1 yl)methanone 3.33-3.35 (m, 2H),2.80-2.82 (m, 2H), [M + H]⁺ 2.67-2.69 (m, 2H), 1.90 (s, 3H). ExampleN-isopropyl-4-[(6- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ MS 321 {[5- ppm8.62-8.56 (m, 1H), 8.48 (d, J = 8.4 Hz, (ESI) (trifluoromethyl)pyridin-1H), 8.30 (dt, J = 8.7, 2.4 Hz, 1H), 8.11 (dd, J = 9.1, m/z 2- 6.0 Hz,1H), 7.89 (t, J = 2.2 Hz, 1H), 488.1 yl]oxy}quinolin-2- 7.78-7.65 (m,2.5H), 7.53 (d, J = 7.9 Hz, [M + H]⁺ yl)carbonyl]piperazine- 0.5H), 7.39(d, J = 8.7 Hz, 1H), 4.48 (dd, J = 12.5, 2-carboxamide 2.7 Hz, 0.5H),4.06-3.97 (m, 0.5H), 3.96-3.83 (m, 0.5H), 3.81-3.67 (m, 1H), 3.58 (d, J= 13.2 Hz, 0.5H), 3.24-3.07 (m, 2H), 3.02-2.81 (m, 1.5H), 2.80-2.62 (m,1.5H), 1.10 (dd, J = 6.6, 2.4 Hz, 3H), 1.00 (dd, J = 16.8, 6.6 Hz, 3H).Example N-methyl-4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ MS 322(trifluoromethyl)pyridin- ppm 8.62-8.57 (m, 1H), 8.48 (d, J = 8.6 Hz,(ESI) 2- 1H), 8.32-8.27 (m, 1H), 8.11 (dd, J = 9.1, 4.2 Hz, m/zyl]oxy}quinolin-2- 1H), 7.93-7.87 (m, 1.5H), 460.1yl)carbonyl]piperazine- 7.81-7.74 (m, 0.5H), 7.74-7.67 (m, 2H), 7.40 (d,J = 8.8 Hz, [M + H]⁺ 2-carboxamide 1H), 4.55-4.47 (m, 0.5H), 4.12-4.02(m, 0.5H), 3.73 (d, J = 10.4 Hz, 0.5H), 3.59 (d, J = 13.1 Hz, 0.5H),3.30-3.21 (m, 2H), 3.20-3.08 (m, 1H), 3.02-2.94 (m, 0.5H), 2.92-2.80 (m,1.5H), 2.64 (d, J = 4.7 Hz, 1.5H), 2.52 (d, J = 4.7 Hz, 1.5H). Examplerac-[(3R,4S)-3,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 323dihydroxy-2,5- 8.60 (bs, 1H), 8.48 (dd, J = 8.5, 2.4 Hz, 1H), 448.1dimethylpyrrolidin-1- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.14 (d, J = 9.2Hz, [M + H]⁺ yl](6-{[5- 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.80-7.67 (m,(trifluoromethyl)pyridin- 2H), 7.40 (d, J = 8.7 Hz, 1H), 5.02-4.88 (m,2- 2H), 4.73 and 4.58 (2m, 1H), 4.33 and yl]oxy}quinolin-2- 4.23 (2m,1H), 4.12 and 3.93 (2m, 1H), 3.80 and yl)methanone 3.74 (2m, 1H), 1.38and 1.27 (2d, J = 6.7 Hz, 3H), 0.74 and 0.69 (2d, J = 6.7 Hz, 3H).Example [cis-3,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 324dimethoxypyrrolidin- 8.59 (bs, 1H), 8.51-8.45 (m, 1H), 8.31 (dd, J =8.7, 448.1 1-yl](6-{[5- 2.6 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.92-7.84 (m, 2H), 7.72 (dd, J = 9.0, 2.6 Hz,1H), 2- 7.43-7.34 (m, 1H), 4.08-3.92 (m, 3H), yl]oxy}quinolin-2-3.85-3.76 (m, 1H), 3.70 (dd, J = 12.6, 5.5 Hz, yl)methanone 1H),3.62-3.55 (m, 1H), 3.38 (s, 3H), 3.30 (s, 3H). Example (3S)-1-[(6-{[5-¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCI m/z 325(trifluoromethyl)pyridin- ppm 1.40-1.75 (m, 2.6H), 1.88 (dd, J = 53.5,445.0 2- 13.0 Hz, 1.4H), 2.30-2.49 (m, 1H), 2.97 (ddd, [M + H]⁺yl]oxy}quinolin-2- J = 34.9, 23.4, 12.3 Hz, 1.56H), 3.20 (dt, J = 15.6,yl)carbonyl]piperidine- 7.8 Hz, 0.5H), 3.67 (dt, J = 37.3, 18.7 Hz,3-carboxamide 1H), 4.37 (d, J = 12.6 Hz, 0.5H), 4.55 (d, J = 13.0 Hz,0.5H), 6.82 (s, 0.5H), 6.94 (s, 0.5H), 7.29-7.53 (m, 2H), 7.70 (ddd, J =20.1, 11.4, 5.8 Hz, 2H), 7.89 (d, J = 2.6 Hz, 1H), 8.12 (dd, J = 11.3,9.2 Hz, 1H), 8.30 (dt, J = 8.6, 2.6 Hz, 1H), 8.48 (dd, J = 8.4, 2.0 Hz,1H), 8.59 (dd, J = 2.8, 1.8 Hz, 1H) Example N-(2-hydroxyethyl)- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.83 (t, MS 326 6-{[5- J = 5.8 Hz, 1H),8.61-8.62 (m, 1H), 8.54 (d, (ESI) (trifluoromethyl)pyridin- J = 8.5 Hz,1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z 2- 8.11-8.22 (m, 2H), 7.93 (d,J = 2.5 Hz, 1H), 378.1 yl]oxy}quinoline-2- 7.76 (dd, J = 9.2, 2.8 Hz,1H), 7.41 (d, J = 8.5 Hz, [M + H]⁺ carboxamide 1H), 4.86 (t, 5.3 Hz,1H), 3.58-3.62 (m, 2H), 3.45-3.49 (m, 2H). Example N-(tetrahydro-2H- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.77 (d, MS 327 pyran-4-yl)-6-{[5- J = 8.2Hz, 1H), 8.61-8.62 (m, 1H), 8.53 (d, (ESI) (trifluoromethyl)pyridin- J =8.2 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z 2- 8.24 (d, J = 9.2 Hz,1H), 8.18 (d, J = 8.5 Hz, 1H), 418.1 yl]oxy}quinoline-2- 7.93 (d, J =2.8 Hz, 1H), 7.76 (dd, J = 9.0, 2.6 Hz, [M + H]⁺ carboxamide 1H), 7.41(d, J = 8.9 Hz, 1H), 4.05-4.15 (m, 1H), 3.90-3.93 (m, 2H), 3.40-3.46 (m,2H), 1.71-1.81 (m, 4H). Example 6-{[2-(piperazin-1- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.67 (d, MS 328 ylcarbonyl)quinolin- J = 2.4 Hz, 1H),8.47 (d, J = 8.2 Hz, 1H), (ESI) 6- 8.39 (dd, J = 8.7, 2.3 Hz, 1H), 8.11(d, J = 9.2 Hz, m/z yl]oxy}nicotinonitrile 1H), 7.88 (d, J = 2.4 Hz,1H), 7.64-7.73 (m, 360.1 2H), 7.38 (d, J = 8.5 Hz, 1H), 3.63-3.65 (m,[M + H]⁺ 2H), 3.34-3.36 (m, 2H), 2.79-2.82 (m, 2H), 2.67-2.69 (m, 2H),1.85 (s, 3H). Example 7-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 329(trifluoromethyl)pyridin- 2.85-3.05 (m, 1 H) 3.12-3.27 (m, 2 H) (ESI) 2-3.58-4.19 (m, 4 H) 4.28-4.56 (m, 1 H) 4.57-4.84 (m, 1 m/zyl]oxy}quinolin-2- H) 7.45 (d, J = 8.85 Hz, 1 H) 7.74-7.84 (m, 2 459.0yl)carbonyl]hexahydro[1,3]oxazolo[3, H) 7.96 (t, J = 2.29 Hz, 1 H) 8.19(d, J = 9.16 Hz, [M + H]⁺ 4- 1 H) 8.36 (dd, J = 8.85, 2.44 Hz, 1 H) 8.56(dd, a]pyrazin-3-one J = 8.54, 2.14 Hz, 1 H) 8.61-8.69 (m, 1 H) Example(4,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 330 difluoropiperidin-1-2.01-2.23 (m, 4H), 3.61 (dd, J = 18.3, 12.7 Hz, 2H), 438.0 yl)(6-{[5-3.78-3.89 (m, 2H), 7.39 (d, J = 8.7 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.65-7.82 (m, 2H), 7.90 (d, J = 2.6 Hz, 1H),2- 8.12 (d, J = 9.1 Hz, 1H), 8.30 (dd, J = 8.7, 2.6 Hz,yl]oxy}quinolin-2- 1H), 8.50 (d, J = 8.5 Hz, 1H), yl)methanone 8.56-8.63(m, 1H) Example N-[(3R)-pyrrolidin-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS331 yl]-6-{[5- 8.61-8.62 (m, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.32 (dd,(ESI) (trifluoromethyl)pyridin- J = 8.7, 2.6 Hz, 1H), 8.23 (d, J = 9.2Hz, 1H), m/z 2- 8.18 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H),403.1 yl]oxy}quinoline-2- 7.78 (dd, J = 9.2, 2.8 Hz, 1H), 7.41 (d, J =8.9 Hz, [M + H]⁺ carboxamide 1H), 4.66-4.74 (m, 1H), 3.41-3.53 (m, 2H),3.22-3.37 (m, 2H), 2.26-2.35 (m, 1H), 2.08-2.17 (m, 1H). Example (6-{[5-¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 332 (trifluoromethyl)pyridin-2.60-2.86 (m, 2H), 3.32-3.50 (m, 6H), 563.0 2- 3.56-3.70 (m, 2H),3.73-3.89 (m, 2H), 7.40 (d, J = 8.6 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H),7.67-7.82 (m, 2H), 7.91 (d, J = 2.6 Hz, yl){4-[(3,3,3- 1H), 8.13 (d, J =9.1 Hz, 1H), 8.31 (dd, J = 8.7, trifluoropropyl)sulfonyl]piperazin- 2.6Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 1- 8.59 (dd, J = 1.6, 0.8 Hz, 1H)yl}methanone Example (8aR)-7-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆,rotamers) δ DCI m/z 333 (trifluoromethyl)pyridin- ppm 2.90 (dt, J =21.4, 8.2 Hz, 1H), 459.0 2- 3.04-3.24 (m, 2H), 3.57 (t, J = 10.8 Hz,0.5H), [M + H]⁺ yl]oxy}quinolin-2- 3.76 (dd, J = 13.3, 3.3 Hz, 0.5H),3.86 (dd, J = 8.9, yl)carbonyl]hexahydro[1, 5.4 Hz, 1H), 3.91-4.16 (m,2H), 4.28 (t, J = 8.5 Hz, 3]oxazolo[3,4- 0.5H), 4.46 (t, J = 8.6 Hz,0.5H), a]pyrazin-3-one 4.57 (d, J = 12.8 Hz, 0.5H), 4.72 (dd, J = 12.6,3.3 Hz, 0.5H), 7.40 (d, J = 8.7 Hz, 1H), 7.74 (ddd, J = 9.2, 6.9, 3.2Hz, 2H), 7.90 (t, J = 2.4 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.31 (dd, J= 8.7, 2.5 Hz, 1H), 8.51 (dd, J = 8.5, 2.2 Hz, 1H), 8.59 (s, 1H) ExampleN-(3-hydroxy-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.99 (t, MS 334methylbutyl)-6-{[5- J = 5.7 Hz, 1H), 8.61 (d, J = 3.0 Hz, 1H), (ESI)(trifluoromethyl)pyridin- 8.53 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7,2.6 Hz, m/z 2- 1H), 8.20-8.13 (m, 2H), 7.92 (d, J = 2.6 Hz, 420.0yl]oxy}quinoline-2- 1H), 7.75 (dd, J = 9.1, 2.6 Hz, 1H), 7.40 (d, J =8.6 Hz, [M + H]⁺ carboxamide 1H), 4.47 (s, 1H), 3.52-3.43 (m, 2H), 1.71(t, J = 7.4 Hz, 2H), 1.18 (s, 6H). Example N-[(2R)-pyrrolidin-2- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.81 (t, MS 335 ylmethyl]-6-{[5- J = 5.8 Hz,1H), 8.61 (d, J = 3.1 Hz, 1H), (ESI) (trifluoromethyl)pyridin- 8.54 (d,J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, m/z 2- 1H), 8.23-8.16 (m,2H), 7.93 (d, J = 2.6 Hz, 417.1 yl]oxy}quinoline-2- 1H), 7.75 (dd, J =9.1, 2.6 Hz, 1H), 7.40 (d, J = 8.7 Hz, [M + H]⁺ carboxamide 1H),3.46-3.36 (m, 2H), 3.25-3.08 (m, 2H), 3.11-2.71 (m, 2H), 1.95-1.52 (m,3H), 1.47-1.21 (m, 1H). Example N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ ppmMS 336 hydroxycyclobutyl)methyl]- 8.63-8.53 (m, 3H), 8.31 (dd, J = 8.7,2.6 Hz, 1H), (ESI) 6-{[5- 8.25-8.18 (m, 2H), 7.94 (d, J = 2.6 Hz, 1H),m/z (trifluoromethyl)pyridin- 7.76 (dd, J = 9.1, 2.7 Hz, 1H), 7.41 (d, J= 8.7 Hz, 418.0 2- 1H), 5.46 (s, 1H), 3.54 (d, J = 6.0 Hz, 2H), [M + H]⁺yl]oxy}quinoline-2- 2.20-1.90 (m, 4H), 1.78-1.44 (m, 2H). carboxamideExample N-[2-(2- ¹H NMR (400 MHz, DMSO-d₆₎ δ ppm 9.01 (t, MS 337oxopyrrolidin-1- J = 6.0 Hz, 1H), 8.60-8.61 (m, 1H), 8.53 (d, (ESI)yl)ethyl]-6-{[5- J = 8.6 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.15-8.19 (m, 2H), 7.93 (d, J = 2.4 Hz, 1H),445.1 2- 7.76 (dd, J = 9.2, 2.4 Hz, 1H), 7.40 (d, J = 8.9 Hz, [M + H]⁺yl]oxy}quinoline-2- 1H), 3.42-3.53 (m, 6H), 2.15-2.19 (m, 2H),carboxamide 1.87-1.94 (m, 2H). Example N-(2-aminoethyl)-6- ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.95 (t, MS 338 {[5- J = 5.9 Hz, 1H), 8.62-8.59 (m,1H), 8.53 (d, J = 8.6 Hz, (ESI) (trifluoromethyl)pyridin- 1H), 8.31 (dd,J = 8.7, 2.6 Hz, 1H), m/z 2- 8.19 (dd, J = 8.8, 6.9 Hz, 2H), 7.93 (d, J= 2.6 Hz, 377.0 yl]oxy}quinoline-2- 1H), 7.75 (dd, J = 9.1, 2.6 Hz, 1H),[M + H]⁺ carboxamide 7.40 (d, J = 8.8 Hz, 1H), 3.43 (q, J = 6.3 Hz, 2H),2.82 (t, J = 6.4 Hz, 2H). Example [2- 1H NMR (400 MHz, DMSO-d₆) δ ppm MS339 (hydroxymethyl)morpholin- 2.97-3.09 (m, 1 H) 3.19-3.29 (m, 1 H)(ESI) 4-yl](6-{[5- 3.37-3.62 (m, 4 H) 3.67-4.03 (m, 2 H) 4.33-4.58 (m, 1m/z (trifluoromethyl)pyridin- H) 4.63-4.92 (m, 1 H) 7.39 (d, J = 8.24Hz, 1 434.0 2- H) 7.67-7.76 (m, 2 H) 7.90 (d, J = 2.44 Hz, 1 [M + H]⁺yl]oxy}quinolin-2- H) 8.12 (d, J = 8.85 Hz, 1 H) 8.30 (dd, J = 8.70,yl)methanone 2.59 Hz, 1 H) 8.49 (d, J = 8.54 Hz, 1 H) 8.59 (s, 1 H)Example [2- 1H NMR (500 MHz, DMSO-d₆) δ ppm MS 340(fluoromethyl)morpholin- 2.85-3.11 (m, 1 H) 3.15-3.30 (m, 1 H) (ESI)4-yl](6-{[5- 3.52-3.66 (m, 1 H) 3.71-3.90 (m, 3 H) 4.32-4.65 (m, 3 m/z(trifluoromethyl)pyridin- H) 7.40 (d, J = 8.54 Hz, 1 H) 7.69-7.78 (m, 2436.0 2- H) 7.90 (d, J = 2.44 Hz, 1 H) 8.12 (d, J = 9.16 Hz, [M + H]⁺yl]oxy}quinolin-2- 1 H) 8.31 (dd, J = 8.85, 2.44 Hz, 1 H) yl)methanone8.50 (d, J = 8.54 Hz, 1 H) 8.59 (s, 1 H) Example (1-hydroxy-7- 1H NMR(500 MHz, DMSO-d₆) δ ppm MS 341 azaspiro[3.5]non-7- 1.19-1.36 (m, 2 H)1.45-1.68 (m, 4 H) (ESI) yl)(6-{[5- 1.70-1.86 (m, 2 H) 2.05-2.18 (m, 1H) 3.22-3.30 (m, 1 m/z (trifluoromethyl)pyridin- H) 3.37-3.50 (m, 1 H)3.75-3.89 (m, 1 H) 458.0 2- 3.91-4.15 (m, 1 H) 4.97 (dd, J = 10.38, 5.80Hz, [M + H]⁺ yl]oxy}quinolin-2- 1 H) 7.39 (dd, J = 8.70, 2.29 Hz, 1 H)yl)methanone 7.65 (d, J = 8.54 Hz, 1 H) 7.68-7.73 (m, 1 H) 7.84-7.95 (m,1 H) 8.04-8.18 (m, 1 H) 8.26-8.37 (m, 1 H) 8.47 (dd, J = 8.39, 4.12 Hz,1 H) 8.59 (s, 1 H) Example 6-[(6-{[5- 1H NMR (400 MHz, DMSO-d₆) δ ppm MS342 (trifluoromethyl)pyridin- 2.70-2.83 (m, 2 H) 3.72 (t, J = 5.65 Hz, 1H) 3.97 (t, (ESI) 2- J = 5.80 Hz, 1 H) 4.35 (s, 1 H) 4.53 (s, 1 H) m/zyl]oxy}quinolin-2- 7.40 (d, J = 8.54 Hz, 1 H) 7.69-7.81 (m, 2 H) 468.0yl)carbonyl]-5,6,7,8- 7.89-7.94 (m, 1 H) 8.04-8.18 (m, 2 H) [M + H]⁺tetrahydropyrido[4,3- 8.26-8.34 (m, 1 H) 8.51 (dd, J = 8.55, 4.27 Hz, 1H) d]pyrimidin-4(3H)- 8.60 (d, J = 6.41 Hz, 1 H) 12.48 (s, 1 H) oneExample 4-[(6-{[5- 1H NMR (400 MHz, DMSO-d₆) δ ppm MS 343(trifluoromethyl)pyridin- 1.78-1.96 (m, 2 H) 3.22-3.29 (m, 2 H) 3.59 (t,(ESI) 2- J = 5.65 Hz, 1 H) 3.85 (t, J = 5.80 Hz, 1 H) m/zyl]oxy}quinolin-2- 4.22 (s, 1 H) 4.31 (s, 1 H) 7.36-7.45 (m, 1 H) 431.0yl)carbonyl]-1,4- 7.61-7.76 (m, 3 H) 7.90 (d, J = 2.75 Hz, 1 H) [M + H]⁺diazepan-2-one 8.10 (t, J = 9.77 Hz, 1 H) 8.30 (dd, J = 8.70, 1.98 Hz, 1H) 8.43-8.53 (m, 1 H) 8.56-8.64 (m, 1 H) Example N-(2,2,2- 1H NMR (400MHz, DMSO-d₆) δ ppm MS 344 trifluoroethyl)-6-{[5- 4.09-4.27 (m, 2 H)7.42 (d, J = 8.85 Hz, 1 H) (ESI) (trifluoromethyl)pyridin- 7.79 (dd, J =9.16, 2.44 Hz, 1 H) 7.96 (d, J = 2.75 Hz, m/z 2- 1 H) 8.22 (dd, J =13.12, 8.85 Hz, 2 H) 8.32 (dd, 416.0 yl]oxy}quinoline-2- J = 8.70, 2.59Hz, 1 H) 8.55-8.65 (m, 2 H) [M + H]⁺ carboxamide 9.46 (t, J = 6.71 Hz, 1H) Example (2-hydroxy-6- 1H NMR (400 MHz, DMSO-d₆) δ ppm MS 345azaspiro[3.4]oct-6- 1.74-1.98 (m, 4 H) 2.14-2.37 (m, 2 H) (ESI)yl)(6-{[5- 3.47-3.61 (m, 2 H) 3.66 (d, J = 4.27 Hz, 1 H) m/z(trifluoromethyl)pyridin- 3.70-3.81 (m, 1 H) 3.95-4.25 (m, 1 H)4.92-5.09 (m, 1 444.0 2- H) 7.39 (d, J = 8.54 Hz, 1 H) 7.67-7.75 (m, 1[M + H]⁺ yl]oxy}quinolin-2- H) 7.80-7.91 (m, 2H) 8.14 (dd, J = 9.16,3.66 Hz, yl)methanone 1 H) 8.30 (d, J = 8.85 Hz, 1 H) 8.46 (dd, J =8.54, 3.97 Hz, 1 H) 8.59 (s, 1 H) Example N-(2-fluoroethyl)-6- 1H NMR(400 MHz, DMSO-d₆) δ ppm MS 346 {[5- 3.61-3.81 (m, 2 H) 4.57 (t, J =5.19 Hz, 1 H) 4.69 (t, (ESI) (trifluoromethyl)pyridin- J = 5.19 Hz, 1 H)7.41 (d, J = 8.85 Hz, 1 H) m/z 2- 7.77 (dd, J = 9.16, 2.44 Hz, 1 H) 7.94(d, J = 2.44 Hz, 380.0 yl]oxy}quinoline-2- 1 H) 8.20 (t, J = 9.31 Hz, 2H) 8.31 (dd, J = 8.85, [M + H]⁺ carboxamide 2.44 Hz, 1 H) 8.55 (d, J =8.24 Hz, 1 H) 8.61 (s, 1 H) 9.07 (t, J = 5.95 Hz, 1 H) ExampleN-(2,2-difluoroethyl)- 1H NMR (400 MHz, DMSO-d₆) δ ppm MS 347 6-{[5-3.71-3.90 (m, 2 H) 6.01-6.41 (m, 1 H) 7.41 (d, (ESI)(trifluoromethyl)pyridin- J = 8.54 Hz, 1 H) 7.78 (dd, J = 9.16, 2.75 Hz,1 m/z 2- H) 7.95 (d, J = 2.44 Hz, 1 H) 8.21 (t, J = 9.00 Hz, 398.0yl]oxy}quinoline-2- 2 H) 8.32 (dd, J = 8.70, 2.59 Hz, 1 H) 8.57 (d, [M +H]⁺ carboxamide J = 8.54 Hz, 1 H) 8.62 (s, 1 H) 9.21 (t, J = 6.26 Hz, 1H) Example [(3S,4S)-3-hydroxy- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z348 4- 8.63-8.57 (m, 1H), 8.49 (d, J = 8.5 Hz, 1H), 450.1(methylsulfanyl)pyrrolidin- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.16 (d, J =9.1 Hz, [M + H]⁺ 1-yl](6-{[5- 1H), 7.93-7.85 (m, 2H), 7.73 (dd, J = 9.0,2.6 Hz, (trifluoromethyl)pyridin- 1H), 7.40 (d, J = 8.6 Hz, 1H), 2-5.56-5.43 (m, 1H), 4.31-3.97 (m, 2H), 3.89-3.46 (m, yl]oxy}quinolin-2-3H), 3.28-3.18 (m, 1H), 2.19 and 2.11 (2s, yl)methanone 3H). ExampleN-(1,1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 349 dioxidotetrahydro-9.21-9.10 (m, 1H), 8.64-8.59 (m, 1H), 466.1 2H-thiopyran-3-yl)-6-8.59-8.50 (m, 1H), 8.35-8.29 (m, 1H), 8.23-8.16 (m, [M + H]⁺ {[5- 2H),7.94 (t, J = 3.8 Hz, 1H), 7.85-7.71 (m, (trifluoromethyl)pyridin- 1H),7.46-7.36 (m, 1H), 4.54-4.41 (m, 1H), 2- 3.42-3.26 (m, 2H), 3.22-3.01(m, 2H), yl]oxy}quinoline-2- 2.17-2.04 (m, 1H), 2.03-1.72 (m, 3H).carboxamide Example [cis-3,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (s,ESI m/z 350 dihydroxypiperidin- 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.30 (dd,J = 8.7, 434.1 1-yl](6-{[5- 2.5 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.88(d, [M + H]⁺ (trifluoromethyl)pyridin- J = 2.6 Hz, 1H), 7.69 (ddd, J =20.6, 11.0, 5.6 Hz, 2- 2H), 7.39 (d, J = 8.7 Hz, 1H), 4.86 andyl]oxy}quinolin-2- 4.67 (2d, J = 4.7 Hz, 1H), 4.63 (m, 1H), yl)methanone3.90-3.37 (m, 6H), 1.83-1.55 (m, 2H). Example [trans-3-hydroxy-4- ¹H NMR(400 MHz, DMSO-d₆) δ ppm ESI m/z 351 (methylsulfonyl)pyrrolidin- 8.60(bs, 1H), 8.50 (dd, J = 8.6, 3.9 Hz, 1H), 482.1 1-yl](6-{[5- 8.31 (dd, J= 8.7, 2.7 Hz, 1H), 8.16 (t, J = 9.0 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 7.94-7.88 (m, 2H), 7.74 (dt, J = 9.0, 2.4Hz, 2- 1H), 7.40 (d, J = 8.6 Hz, 1H), yl]oxy}quinolin-2- 5.95-5.84 (m,1H), 4.71-4.59 (m, 1H), 4.39-3.56 (m, yl)methanone 5H), 3.14 and 3.08(2s, 3H). Example 1,4-dioxa-7- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z352 azaspiro[4.4]non-7- 8.59 (bs, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.30(dd, J = 8.7, 446.1 yl(6-{[5- 2.6 Hz, 1H), 8.15 (dd, J = 9.1, 3.1 Hz,[M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.92-7.83 (m, 2H), 7.72 (dd, J =9.1, 2.6 Hz, 2- 1H), 7.40 (d, J = 8.6 Hz, 1H), yl]oxy}quinolin-2-4.01-3.84 (m, 6H), 3.69 (t, J = 7.5 Hz, 1H), 3.61 (s, 1H), yl)methanone2.13-2.05 (m, 2H). Example [4- ¹H NMR (400 MHz, Benzene-d₆) δ ESI m/z353 (methoxyimino)piperidin- 8.27-8.16 (m, 1H), 7.98 (dd, J = 9.3, 5.6Hz, 1H), 445.0 1-yl](6-{[5- 7.71 (dd, J = 8.5, 1.8 Hz, 1H), 7.47 (dd, J= 8.5, 2.5 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.30-7.18 (m,3H), 6.48 (d, J = 8.6 Hz, 2- 1H), 3.80 (d, J = 5.9 Hz, 3H), 3.71 (dt, J= 14.8, yl]oxy}quinolin-2- 6.1 Hz, 2H), 3.44 (dt, J = 19.8, 6.0 Hz,yl)methanone 2H), 2.69 (t, J = 6.0 Hz, 1H), 2.55 (t, J = 6.2 Hz, 1H),2.40-2.33 (m, 1H), 2.31-2.20 (m, 1H). Example (2-hydroxy-7- 1H NMR (400MHz, DMSO-d₆) δ ppm MS 354 azaspiro[3.5]non-7- 1.44-1.55 (m, 2 H)1.55-1.68 (m, 4 H) (ESI) yl)(6-{[5- 2.12-2.25 (m, 2 H) 3.22-3.32 (m, 2H) 3.55-3.68 (m, 2 m/z (trifluoromethyl)pyridin- H) 4.00-4.19 (m, 1 H)4.91-4.98 (m, 1 H) 458.0 2- 7.39 (d, J = 8.54 Hz, 1 H) 7.61-7.74 (m, 2H) [M + H]⁺ yl]oxy}quinolin-2- 7.88 (d, J = 2.44 Hz, 1 H) 8.09 (d, J =8.85 Hz, 1 yl)methanone H) 8.30 (dd, J = 8.70, 2.59 Hz, 1 H) 8.46 (d, J= 8.54 Hz, 1 H) 8.59 (s, 1 H) Example 6-{[5- 1H NMR (500 MHz, DMSO-d₆) δppm MS 355 (trifluoromethyl)pyridin- 2.58-2.72 (m, 2 H) 3.63 (q, J =6.71 Hz, 2 H) 7.41 (d, (ESI) 2-yl]oxy}-N- J = 8.85 Hz, 1 H) 7.77 (dd, J= 9.16, 2.75 Hz, 1 m/z (3,3,3- H) 7.94 (d, J = 2.44 Hz, 1 H) 8.19 (dd, J= 8.85, 430.0 trifluoropropyl)quinoline- 4.88 Hz, 2 H) 8.32 (dd, J =8.70, 2.59 Hz, 1 H) [M + H]⁺ 2-carboxamide 8.55 (d, J = 8.24 Hz, 1 H)8.61 (s, 1 H) 9.15 (t, J = 6.10 Hz, 1 H) Example [(7S,8aR)-7- 1H NMR(400 MHz, DMSO-d₆) δ ppm MS 356 fluorohexahydropyrrolo[1, 1.47-2.13 (m,2 H) 2.24-2.44 (m, 3 H) (ESI) 2-a]pyrazin- 2.57-3.00 (m, 2 H) 3.01-3.24(m, 1 H) 3.48-3.61 (m, 1 m/z 2(1H)-yl](6-{[5- H) 3.80 (dd, J = 60.27,12.66 Hz, 1 H) 4.63 (dd, 461.0 (trifluoromethyl)pyridin- J = 62.71,12.66 Hz, 1 H) 5.08-5.38 (m, 1 H) [M + H]⁺ 2- 7.39 (d, J = 8.54 Hz, 1 H)7.66-7.75 (m, 2 H) yl]oxy}quinolin-2- 7.89 (d, J = 2.44 Hz, 1 H) 8.11(d, J = 9.16 Hz, 1 yl)methanone H) 8.30 (dd, J = 8.85, 2.44 Hz, 1 H)8.49 (d, J = 8.55 Hz, 1 H) 8.58 (s, 1 H) Example [(3R,7S,8aR)-7- 1H NMR(500 MHz, DMSO-d₆) δ ppm 1.32 (t, MS 357 fluoro-3- J = 7.02 Hz, 3 H)1.51-2.13 (m, 2 H) (ESI) methylhexahydropyrrolo[1, 2.16-2.31 (m, 2 H)2.32-2.46 (m, 1 H) m/z 2-a]pyrazin- 2.71-2.81 (m, 1 H) 2.91-3.06 (m, 1H) 3.47-3.58 (m, 1 475.0 2(1H)-yl](6-{[5- H) 3.67-3.98 (m, 1 H)4.59-4.89 (m, 1 H) [M + H]⁺ (trifluoromethyl)pyridin- 5.13-5.37 (m, 1 H)7.39 (d, J = 8.85 Hz, 1 H) 2- 7.64-7.74 (m, 2 H) 7.89 (t, J = 2.14 Hz, 1H) yl]oxy}quinolin-2- 8.11 (dd, J = 9.00, 6.87 Hz, 1 H) 8.30 (dd,yl)methanone J = 8.85, 2.44 Hz, 1 H) 8.48 (dd, J = 8.39, 5.34 Hz, 1 H)8.58 (s, 1 H) Example [(3R,8aR)-7,7- 1H NMR (500 MHz, DMSO-d₆) δ ppm MS358 difluoro-3- 1.37 (dd, J = 6.87, 3.81 Hz, 3 H) 1.80-2.14 (m, 1 H)(ESI) methylhexahydropyrrolo[1, 2.18-2.44 (m, 3 H) 2.45-2.59 (m, 1 H)m/z 2-a]pyrazin- 2.72-3.21 (m, 2 H) 3.35-3.44 (m, 1 H) 493.02(1H)-yl](6-{[5- 3.69-4.02 (m, 1 H) 4.57-4.91 (m, 1 H) 7.39 (d, J = 8.54Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1 H) 7.65-7.74 (m, 2 H) 7.87-7.91(m, 1 2- H) 8.12 (t, J = 8.54 Hz, 1 H) 8.31 (dd, J = 8.54,yl]oxy}quinolin-2- 2.44 Hz, 1 H) 8.45-8.52 (m, 1 H) 8.58 (s, 1yl)methanone H) Example [(7S,8aS)-7- 1H NMR (500 MHz, DMSO-d₆) δ ppm MS359 fluorohexahydropyrrolo[1, 1.30-1.67 (m, 1 H) 1.95-2.48 (m, 4 H)(ESI) 2-a]pyrazin- 2.70-3.06 (m, 2 H) 3.09-3.29 (m, 2 H) 3.80 (dd, m/z2(1H)-yl](6-{[5- J = 60.12, 12.82 Hz, 1 H) 4.64 (dd, J = 63.02, 461.0(trifluoromethyl)pyridin- 12.66 Hz, 1 H) 5.07-5.31 (m, 1 H) 7.39 (d,[M + H]⁺ 2- J = 8.54 Hz, 1 H) 7.66-7.74 (m, 2 H) 7.89 (d,yl]oxy}quinolin-2- J = 2.44 Hz, 1 H) 8.11 (dd, J = 9.16, 3.05 Hz, 1yl)methanone H) 8.30 (dd, J = 8.54, 2.44 Hz, 1 H) 8.48 (dd, J = 8.55,1.83 Hz, 1 H) 8.59 (s, 1 H) Example 1,4,6,7-tetrahydro- 1H NMR (400 MHz,DMSO-d₆) δ ppm MS 360 5H-imidazo[4,5- 2.61-2.83 (m, 2 H) 3.68 (t, J =5.65 Hz, 1 H) 4.03 (t, (ESI) c]pyridin-5-yl(6-{[5- J = 5.49 Hz, 1 H)4.42-4.79 (m, 2 H) 7.40 (d, m/z (trifluoromethyl)pyridin- J = 8.54 Hz, 1H) 7.45-7.59 (m, 1 H) 440.0 2- 7.68-7.77 (m, 2 H) 7.91 (d, J = 2.44 Hz,1 H) 8.14 (d, [M + H]⁺ yl]oxy}quinolin-2- J = 9.16 Hz, 1 H) 8.31 (dd, J= 8.55, 2.44 Hz, 1 yl)methanone H) 8.50 (t, J = 7.78 Hz, 1 H) 8.60 (s, 1H) 11.92 (s, 1 H) Example N-[(4- ¹H NMR (500 MHz, CDCl₃) δ ppm 8.82 (bs,MS 361 benzylmorpholin-3- 1H), 8.46 (bs, 1H), 8.38-8.20 (m, 3H), (ESI)yl)methyl]-6-{[5- 7.99 (dd, J = 8.7, 2.4 Hz, 1H), 7.68 (d, J = 2.5 Hz,m/z (trifluoromethyl)pyridin- 1H), 7.63 (dd, J = 9.1, 2.5 Hz, 1H), 523.22- 7.54-7.49 (m, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.16 (d, J = 8.6 Hz,[M + H]⁺ yl]oxy}quinoline-2- 1H), 4.30-4.21 (m, 1H), carboxamide3.94-3.86 (m, 1H), 3.81-3.74 (m, 2H), 3.69-3.59 (m, 2H), 3.48-3.27 (m,1H), 2.94-2.73 (m, 2H), 2.41-2.15 (m, 1H), 1.42-1.23 (m, 2H), 1.25-0.76(m, 3H). Example N-[(4- ¹H NMR (500 MHz, CDCl₃) δ ppm 8.82 (bs, MS 362hydroxytetrahydro- 1H), 8.46 (bs, 1H), 8.38-8.20 (m, 3H), (ESI)2H-pyran-4- 7.99 (dd, J = 8.7, 2.4 Hz, 1H), 7.68 (d, J = 2.5 Hz, m/zyl)methyl]-6-{[5- 1H), 7.63 (dd, J = 9.1, 2.5 Hz, 1H), 448.0(trifluoromethyl)pyridin- 7.54-7.49 (m, 2H), 7.34 (t, J = 7.4 Hz, 2H),7.16 (d, J = 8.6 Hz, [M + H]⁺ 2- 1H), 4.30-4.21 (m, 1H),yl]oxy}quinoline-2- 3.94-3.86 (m, 1H), 3.81-3.74 (m, 2H), 3.69-3.59 (m,carboxamide 2H), 3.48-3.27 (m, 1H), 2.94-2.73 (m, 2H), 2.41-2.15 (m,1H), 1.42-1.23 (m, 2H), 1.25-0.76 (m, 3H). Example N-[(2S)-pyrrolidin-2-¹H NMR (400 MHz, CDCl₃) δ ppm 9.19 (s, MS 363 ylmethyl]-6-{[5- 1H), 8.40(s, 1H), 8.28 (d, J = 9.2 Hz, 1H), (ESI) (trifluoromethyl)pyridin- 8.17(q, J = 8.7 Hz, 2H), 7.95 (d, J = 8.8 Hz, m/z 2- 1H), 7.56 (d, J = 2.2Hz, 1H), 7.45 (d, J = 9.0 Hz, 417.1 yl]oxy}quinoline-2- 1H), 7.09 (d, J= 8.6 Hz, 1H), 3.77 (s, 3H), [M + H]⁺ carboxamide 3.21 (s, 2H), 2.03 (s,2H), 1.84 (s, 2H), 1.68 (s, 1H). Example N-[2-(3,3- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.89 (t, MS 364 dimethylazetidin-1- J = 6.1 Hz, 1H),8.60-8.61 (m, 1H), 8.52 (d, (ESI) yl)ethyl]-6-{[5- J = 8.5 Hz, 1H), 8.31(dd, J = 8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.13-8.19 (m,2H), 7.91 (d, J = 2.4 Hz, 1H), 445.1 2- 7.73 (dd, J = 9.2, 2.4 Hz, 1H),7.39 (d, J = 8.9 Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H), 3.37-3.40 (m,2H), 3.13 (s, 4H), carboxamide 2.76-2.79 (m, 2H), 1.20 (s, 6H). ExampleN-[2-(thiomorpholin- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.88 (t, MS 3654-yl)ethyl]-6-{[5- J = 5.8 Hz, 1H), 8.60-8.61 (m, 1H), 8.54 (d, (ESI)(trifluoromethyl)pyridin- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.9, 2.4 Hz,1H), m/z 2- 8.17-8.20 (m, 2H), 7.93 (d, J = 2.4 Hz, 1H), 463.1yl]oxy}quinoline-2- 7.76 (dd, J = 9.2, 2.4 Hz, 1H), 7.41 (d, J = 8.9 Hz,[M + H]⁺ carboxamide 1H), 3.47-3.51 (m, 2H), 2.73-2.75 (m, 4H),2.62-2.64 (m, 4H), 2.59 (t, J = 2.6 Hz, 2H). Example N-allyl-N-methyl-6-¹H NMR (500 MHz, CDCl₃) δ ppm 8.45 (bs, MS 366 {[5- 1H), 8.28-8.11 (m,2H), 7.97 (dd, J = 8.7, 2.4 Hz, (ESI) (trifluoromethyl)pyridin- 1H),7.75 (dd, J = 8.4, 5.0 Hz, 1H), 7.62 (t, m/z 2- J = 2.9 Hz, 1H), 7.57(dt, J = 9.1, 2.8 Hz, 1H), 388.1 yl]oxy}quinoline-2- 7.14 (d, J = 8.6Hz, 1H), 6.01-5.88 (m, 1H), [M + H]⁺ carboxamide 5.37-5.26 (m, 1H),5.23-5.15 (m, 1H), 4.25 (d, J = 6.1 Hz, 1H), 4.12 (d, J = 5.8 Hz, 1H),3.17-3.10 (m, 3H). Example 1-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppmESI m/z 367 (trifluoromethyl)pyridin- 8.62-8.58 (m, 1H), 8.51 (d, J =8.6 Hz, 1H), 399.1 2- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.19 (d, J = 9.1Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.91 (d,J = 2.6 Hz, yl)carbonyl]azetidine- 1H), 7.75 (dd, J = 9.0, 2.6 Hz, 1H),3-carbonitrile 7.40 (d, J = 8.7 Hz, 1H), 5.08 (t, J = 9.6 Hz, 1H), 4.98(dd, J = 10.3, 6.1 Hz, 1H), 4.44 (t, J = 9.6 Hz, 1H), 4.30 (dd, J =10.0, 6.0 Hz, 1H), 3.99-3.87 (m, 1H). Example [cis-3-hydroxy-4- ¹H NMR(400 MHz, DMSO-d₆) δ ppm ESI m/z 368 (methoxymethoxy)pyrrolidin- 8.59(bs, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.30 (dd, J = 8.7, 464.11-yl](6-{[5- 2.6 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.90 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 8.5 Hz,1H), 2- 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.40 (d, J = 8.7 Hz,yl]oxy}quinolin-2- 1H), 5.10 (dd, J = 11.5, 4.8 Hz, 1H), yl)methanone4.79-4.66 (m, 2H), 4.32-3.45 (m, 6H), 3.34 and 3.25 (2s, 3H). ExampleN-[(1- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.88 (t, J = 5.9 Hz, MS 369hydroxycyclopropyl)methyl]- 1H), 8.48-8.42 (m, 1H), (ESI) 6-{[5-8.40-8.15 (m, 3H), 8.02-7.94 (m, 1H), 7.65 (dd, J = 6.1, m/z(trifluoromethyl)pyridin- 2.6 Hz, 1H), 7.58 (ddd, J = 10.4, 9.1, 2.6 Hz,404.1 2- 1H), 7.14 (dd, J = 8.6, 4.7 Hz, 1H), 4.13 (d, J = 6.0 Hz, [M +H]⁺ yl]oxy}quinoline-2- 1H), 1.42-1.01 (m, 4H), carboxamide 1.02-0.77(m, 2H). Example 1-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 370(trifluoromethyl)pyridin- 8.60 (dd, J = 2.7, 1.3 Hz, 1H), 8.53 (d, J =8.5 Hz, 386.0 2- 1H), 8.31 (dd, J = 8.6, 2.6 Hz, 1H), 8.20 (d, J = 9.0Hz, [M − H]⁻ yl]oxy}quinolin-2- 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.92 (d,yl)carbonyl]azetidin- J = 2.6 Hz, 1H), 7.75 (dd, J = 9.1, 2.6 Hz, 1H),3-one 7.41 (d, J = 8.6 Hz, 1H), 5.55-5.50 (m, 2H), 5.02-4.97 (m, 2H).Example N-(4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.79 (d, ESI m/z 371hydroxytetrahydrofuran- J = 7.4 Hz, 1H), 8.64-8.59 (m, 1H), 8.54 (d, J =8.5 Hz, 420.1 3-yl)-6-{[5- 1H), 8.35-8.28 (m, 1H), 8.23 (d, J = 9.1 Hz,[M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.17 (d, J = 8.5 Hz, 1H), 2-7.93 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1, 2.6 Hz, yl]oxy}quinoline-2-1H), 7.40 (d, J = 8.6 Hz, 1H), 5.37 (d, J = 3.4 Hz, carboxamide 1H),4.36 (m, 1H), 4.26 (m, 1H), 4.08-3.96 (m, 2H), 3.74 (dd, J = 9.0, 3.8Hz, 1H), 3.57 (dd, J = 9.3, 2.7 Hz, 1H). Example 5-{[2-(piperazin-1- ¹HNMR (400 MHz, DMSO-d₆₎ δ ppm MS 372 ylcarbonyl)quinolin- 8.97 (br s,2H), 8.87 (d, J = 1.2 Hz, 1H), 8.82 (d, (ESI) 6-yl]oxy}pyrazine-2- J =1.5 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.16 (d, m/z carbonitrile J = 9.2Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 361.1 7.79-7.82 (m, 2H), 3.91-3.93(m, 2H), 3.78-3.80 (m, [M + H]⁺ 2H), 3.27-3.30 (m, 2H), 3.16-3.20 (m,2H). Example [cis-2,2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 373dimethyltetrahydro- 8.60 (dd, J = 2.7, 1.3 Hz, 1H), 8.53 (d, J = 8.5 Hz,386.0 5H-[1,3]dioxolo[4,5- 1H), 8.31 (dd, J = 8.6, 2.6 Hz, 1H), 8.20 (d,J = 9.0 Hz, [M − H]⁻ c]pyrrol-5-yl](6-{[5- 1H), 8.16 (d, J = 8.5 Hz,1H), 7.92 (d, (trifluoromethyl)pyridin- J = 2.6 Hz, 1H), 7.75 (dd, J =9.1, 2.6 Hz, 1H), 2- 7.41 (d, J = 8.6 Hz, 1H), 5.55-5.50 (m, 2H),yl]oxy}quinolin-2- 5.02-4.97 (m, 2H). yl)methanone Example {2- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.79 (d, ESI m/z 374[(dimethylamino)methyl]morpholin- J = 7.4 Hz, 1H), 8.64-8.59 (m, 1H),8.54 (d, J = 8.5 Hz, 420.1 4- 1H), 8.35-8.28 (m, 1H), 8.23 (d, J = 9.1Hz, [M + H]⁺ yl}(6-{[5- 1H), 8.17 (d, J = 8.5 Hz, 1H),(trifluoromethyl)pyridin- 7.93 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1,2.6 Hz, 2- 1H), 7.40 (d, J = 8.6 Hz, 1H), 5.37 (d, J = 3.4 Hz,yl]oxy}quinolin-2- 1H), 4.36 (m, 1H), 4.26 (m, 1H), yl)methanone4.08-3.96 (m, 2H), 3.74 (dd, J = 9.0, 3.8 Hz, 1H), 3.57 (dd, J = 9.3,2.7 Hz, 1H). Example 1-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.48 (t,DCI m/z 375 (trifluoromethyl)pyridin- J = 6.2 Hz, 2H), 2.56 (t, J = 6.4Hz, 2H), 416.0 2- 3.79 (t, J = 6.2 Hz, 2H), 3.92-4.07 (m, 2H), [M + H]⁺yl]oxy}quinolin-2- 7.40 (d, J = 8.8 Hz, 1H), 7.68-7.85 (m, 2H),yl)carbonyl]piperidin- 7.89 (dd, J = 14.4, 5.3 Hz, 1H), 8.13 (d, J = 9.1Hz, 4-one 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.50 (t, J = 9.3 Hz, 1H),8.55-8.65 (m, 1H) Example N,N-di(tetrahydro- ¹H NMR (400 MHz, CDCl₃)δ8.45 (s, 1H), DCI m/z 376 2H-pyran-4-yl)-6- 8.23 (d, 1H, 8.6 Hz), 8.1(d, 1H, J = 8.9 Hz), 502.1 {[5- 7.98 (dd, 1H, J = 6.3, 2.5 Hz), 7.68 (d,1H, 8.5 Hz), [M + H]⁺ (trifluoromethyl)pyridin- 7.63 (d, 1H, J = 2.5),7.57 (dd, 1H, J = 6.5, 2- 2.5 Hz), 7.15 (d, 1H, 8.5 Hz),yl]oxy}quinoline-2- 4.00-4.10 (m), 3.45 (m), 3.05-3.20 (m) carboxamideExample {4-[(1S,4S)-2-oxa-5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 377azabicyclo[2.2.1]hept- 1.36 (dt, J = 19.3, 6.3 Hz, 2H), 1.60 (t, J = 7.8Hz, 499.0 5-yl]piperidin-1- 1H), 1.72 (dd, J = 30.0, 11.3 Hz, 2H), 1.90(t, J = 15.6 Hz, [M + H]⁺ yl}(6-{[5- 1H), 2.32 (dd, J = 23.0, 9.6 Hz,(trifluoromethyl)pyridin- 1H), 2.65 (s, 1H), 2.93 (dd, J = 24.4, 8.7 Hz,2- 1H), 3.15 (dd, J = 24.0, 12.0 Hz, 2H), 3.49 (dd, yl]oxy}quinolin-2- J= 19.0, 7.1 Hz, 1H), 3.64 (dd, J = 33.2, 20.1 Hz, yl)methanone 2H), 3.88(dd, J = 19.5, 7.6 Hz, 1H), 4.31 (t, J = 11.6 Hz, 2H), 7.39 (d, J = 8.7Hz, 1H), 7.60-7.75 (m, 2H), 7.88 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 9.1,3.0 Hz, 1H), 8.30 (dd, J = 8.7, 2.3 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H),8.59 (s, 1H) Example {4-[(1R,4R)-2-oxa-5- ¹H NMR (400 MHz, DMSO-d₆) δppm DCI m/z 378 azabicyclo[2.2.1]hept- 1.38 (dd, J = 19.7, 12.8 Hz, 2H),1.53-1.83 (m, 499.0 5-yl]piperidin-1- 3H), 1.90 (t, J = 13.7 Hz, 1H),2.32 (dd, J = 18.4, [M + H]⁺ yl}(6-{[5- 9.6 Hz, 1H), 2.65 (t, J = 9.2Hz, 1H), (trifluoromethyl)pyridin- 2.93 (dd, J = 19.5, 8.6 Hz, 1H), 3.15(dd, J = 21.9, 2- 10.9 Hz, 2H), 3.49 (dd, J = 15.2, 7.2 Hz,yl]oxy}quinolin-2- 1H), 3.58-3.73 (m, 2H), 3.88 (dd, J = 15.6,yl)methanone 7.6 Hz, 1H), 4.29 (d, J = 14.6 Hz, 2H), 7.39 (d, J = 8.7Hz, 1H), 7.63-7.77 (m, 2H), 7.88 (d, J = 2.6 Hz, 1H), 8.10 (dd, J = 9.1,2.3 Hz, 1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H),8.60 (d, J = 13.0 Hz, 1H) Example N,N-bis(2- ¹H NMR (400 MHz, CDCl₃) δppm 8.45 (s, DCI m/z 379 methoxyethyl)-6-{[5- 1H), 8.20 (d, 1H). 8.14(d, 1H), 7.97 (d, 1H), 450.1 (trifluoromethyl)pyridin- 7.76 (dd, 1H),7.6 (d, 1H), 7.55 (dd, 1H), [M + H]⁺ 2- 7.15 (d, 1H), 3.86 (t, 2H), 3.81(t, 2H), 3.745 (t, yl]oxy}quinoline-2- 2H), 3.63 (t, 2H), 3.42 (s, 3H),3.26 (s, 3H) carboxamide Example N-[1- ¹H NMR (400 MHz, DMSO-d₆) δ ppmDCI m/z 380 (hydroxymethyl)cyclopropyl]- 0.77-0.93 (m, 4H), 3.58 (d, J =5.7 Hz, 2H), 4.81 (t, 404.0 6-{[5- J = 5.7 Hz, 1H), 7.40 (d, J = 8.6 Hz,1H), [M + H]⁺ (trifluoromethyl)pyridin- 7.75 (dd, J = 9.1, 2.6 Hz, 1H),7.92 (d, J = 2.6 Hz, 2- 1H), 8.18 (dd, J = 17.9, 8.8 Hz, 2H), 8.31 (dd,yl]oxy}quinoline-2- J = 8.7, 2.5 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H),carboxamide 8.58-8.66 (m, 1H), 8.89 (s, 1H) Example [4-(tetrahydrofuran-¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 381 3- ppm 8.53 (s, 1H), 8.46(d, J = 8.5 Hz, 1H), (APCI) ylsulfonyl)piperazin- 8.22 (dd, J = 8.7, 2.5Hz, 1H), 8.13 (d, J = 9.1 Hz, m/z 1-yl](6-{[5- 1H), 7.82 (d, J = 2.6 Hz,1H), 7.72 (d, J = 8.5 Hz, 537.0 (trifluoromethyl)pyridin- 1H), 7.68 (dd,J = 9.1, 2.7 Hz, 1H), [M + H]⁺ 2- 7.33 (d, J = 8.7 Hz, 1H), 4.08-3.81(m, 4H), yl]oxy}quinolin-2- 3.80-3.57 (m, 5H), 3.38 (s, 4H),yl)methanone 2.34-2.22 (m, 1H), 2.22-2.07 (m, 1H). Example methyl({4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 382(trifluoromethyl)pyridin- ppm 8.53 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H),(APCI) 2- 8.22 (dd, J = 8.8, 2.5 Hz, 1H), 8.13 (d, J = 9.1 Hz, m/zyl]oxy}quinolin-2- 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 8.5,539.0 yl)carbonyl]piperazin- 2.6 Hz, 1H), 7.69 (dd, J = 9.1, 2.7 Hz,[M + H]⁺ 1-yl}sulfonyl)acetate 1H), 7.33 (d, J = 8.7 Hz, 1H), 4.26 (s,2H), 3.75 (d, J = 6.2 Hz, 7H), 3.49 (s, 1H), 3.39 (s, 3H). Example[4-(tetrahydro-2H- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 383pyran-4- ppm 8.53 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), (APCI)ylsulfonyl)piperazin- 8.22 (dd, J = 8.7, 2.6 Hz, 1H), 8.12 (d, J = 9.1Hz, m/z 1-yl](6-{[5- 1H), 7.82 (d, J = 2.6 Hz, 1H), 551.0(trifluoromethyl)pyridin- 7.75-7.64 (m, 2H), 7.33 (d, J = 8.7 Hz, 1H),3.94 (dd, J = 11.8, [M + H]⁺ 2- 2.9 Hz, 2H), 3.71 (s, 4H), 3.51-3.33 (m,yl]oxy}quinolin-2- 7H), 1.99-1.85 (m, 2H), 1.69 (qd, J = 11.9,yl)methanone 4.7 Hz, 2H). Example (4-{[1-(2- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 384 methoxyethyl)-1H- ppm 8.52 (dd, J = 1.6,0.8 Hz, 1H), 8.44 (d, J = 8.4 Hz, (APCI) pyrazol-4- 1H), 8.25-8.20 (m,2H), 8.08 (d, J = 9.1 Hz, m/z yl]sulfonyl}piperazin- 1H), 7.83-7.78 (m,2H), 591.0 1-yl)(6-{[5- 7.70-7.63 (m, 2H), 7.32 (d, J = 8.6 Hz, 1H),4.35 (t, J = 5.3 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 2H), 3.81-3.65(m, 6H), 3.25 (s, 3H), 2- 3.07 (s, 4H). yl]oxy}quinolin-2- yl)methanoneExample {4-[(tetrahydrofuran- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS385 3- ppm 8.56-8.50 (m, 1H), 8.46 (d, J = 8.5 Hz, (APCI)ylmethyl)sulfonyl]piperazin- 1H), 8.22 (dd, J = 8.7, 2.6 Hz, 1H), 8.13(d, J = 9.1 Hz, m/z 1-yl}(6-{[5- 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.72 (d,551.0 (trifluoromethyl)pyridin- J = 8.5 Hz, 1H), 7.68 (dd, J = 9.1, 2.6Hz, 1H), [M + H]⁺ 2- 7.33 (d, J = 8.6 Hz, 1H), 3.87 (dd, J = 8.6, 7.2Hz, yl]oxy}quinolin-2- 1H), 3.82-3.60 (m, 6H), 3.45 (dd, J = 8.6,yl)methanone 6.8 Hz, 1H), 3.34 (s, 4H), 3.20 (dd, J = 7.0, 5.6 Hz, 2H),2.68-2.55 (m, 1H), 2.19-2.08 (m, 1H), 1.77-1.64 (m, 1H). Example{4-[(1,1- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 386dioxidotetrahydrothiophen- ppm 8.53 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H),(APCI) 3- 8.22 (dd, J = 8.7, 2.7 Hz, 1H), 8.13 (d, J = 9.1 Hz, m/zyl)sulfonyl]piperazin- 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.72 (d, J = 8.5Hz, 584.9 1-yl}(6-{[5- 1H), 7.69 (dd, J = 9.1, 2.7 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.33 (d, J = 8.6 Hz, 1H), 4.28 (dd, J = 9.0,7.0 Hz, 2- 1H), 3.74 (s, 4H), 3.59 (dd, J = 13.7, 8.9 Hz,yl]oxy}quinolin-2- 1H), 3.43 (s, 4H), 3.36-3.29 (m, 1H), yl)methanone3.23-3.13 (m, 2H), 2.64-2.54 (m, 1H), 2.41-2.27 (m, 1H). Example{4-[(1-methyl-1H- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 387pyrazol-4- ppm 8.52 (d, J = 0.9 Hz, 1H), 8.44 (d, J = 8.4 Hz, (APCI)yl)sulfonyl]piperazin- 1H), 8.25-8.19 (m, 2H), 8.09 (d, J = 9.1 Hz, m/z1-yl}(6-{[5- 1H), 7.81 (d, J = 2.6 Hz, 1H), 7.76 (s, 1H), 547.0(trifluoromethyl)pyridin- 7.67 (dd, J = 8.9, 2.7 Hz, 2H), 7.32 (d, J =8.7 Hz, [M + H]⁺ 2- 1H), 3.92 (s, 3H), 3.74 (s, 4H), 3.06 (s,yl]oxy}quinolin-2- 4H). yl)methanone Example N-[4-methyl-5-({4- ¹H NMR(400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 388 [(6-{[5- ppm 8.52 (s, 1H), 8.44(d, J = 8.5 Hz, 1H), (APCI) (trifluoromethyl)pyridin- 8.22 (dd, J = 8.7,2.5 Hz, 1H), 8.08 (d, J = 9.1 Hz, m/z 2- 1H), 7.81 (d, J = 2.6 Hz, 1H),621.0 yl]oxy}quinolin-2- 7.71-7.63 (m, 2H), 7.32 (d, J = 8.7 Hz, 1H),3.76 (s, 4H), [M + H]⁺ yl)carbonyl]piperazin- 3.22 (s, 4H), 2.50 (s,3H), 2.19 (s, 3H). 1-yl}sulfonyl)-1,3- thiazol-2- yl]acetamide ExampleN-[5-({4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆/D₂O, 90° C.) δ MS 389(trifluoromethyl)pyridin- ppm 8.53 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H),(APCI) 2- 8.22 (dd, J = 8.7, 2.7 Hz, 1H), 8.08 (d, J = 9.1 Hz, m/zyl]oxy}quinolin-2- 1H), 7.95 (s, 1H), 7.81 (d, J = 2.6 Hz, 1H), 606.9yl)carbonyl]piperazin- 7.71-7.61 (m, 2H), 7.32 (d, J = 8.7 Hz, 1H), [M +H]⁺ 1-yl}sulfonyl)-1,3- 3.77 (s, 4H), 3.19 (s, 4H), 2.22 (s, 3H).thiazol-2- yl]acetamide Example {4-[(1,5-dimethyl- ¹H NMR (400 MHz,DMSO-d₆/D₂O, 90° C.) δ MS 390 1H-pyrazol-4- ppm 8.55-8.50 (m, 1H), 8.44(d, J = 8.6 Hz, (APCI) yl)sulfonyl]piperazin- 1H), 8.22 (dd, J = 8.7,2.6 Hz, 1H), 8.09 (d, J = 9.1 Hz, m/z 1-yl}(6-{[5- 1H), 7.81 (d, J = 2.6Hz, 1H), 561.0 (trifluoromethyl)pyridin- 7.70-7.64 (m, 3H), 7.32 (d, J =8.7 Hz, 1H), 3.80 (s, [M + H]⁺ 2- 3H), 3.73 (s, 4H), 3.07 (s, 4H), 2.44(s, 3H). yl]oxy}quinolin-2- yl)methanone Example N-[(3S)- ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.88 (d, MS 391 tetrahydrofuran-3-yl]- J = 7.0 Hz,1H), 8.61-8.62 (m, 1H), 8.54 (d, (ESI) 6-{[5- J = 8.5 Hz, 1H), 8.31 (dd,J = 8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.24 (d, J = 9.2 Hz,1H), 8.16 (d, J = 8.6 Hz, 1H), 404.1 2- 7.92 (d, J = 2.8 Hz, 1H), 7.76(dd, J = 9.2, 2.8 Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H), 7.40 (d, J = 8.5Hz, 1H), 4.53-4.60 (m, carboxamide 1H), 3.85-3.96 (m, 2H), 3.69-3.79 (m,2H), 2.20-2.28 (m, 1H), 2.02-2.10 (m, 1H). Example N-(2-methoxyethyl)-¹H NMR (400 MHz, DMSO-d₆) 1:1 rotamers δ MS 392 N-methyl-6-{[5- ppm8.59-8.60 (m, 1H), 8.45-8.49 (m, 1H), (ESI) (trifluoromethyl)pyridin-8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.09-8.14 (m, m/z 2- 1H), 7.87-7.89 (m,1H), 7.65-7.72 (m, 2H), 406.1 yl]oxy}quinoline-2- 7.39 (d, J = 8.9 Hz,1H), 3.69-3.71 (m, 1H), [M + H]⁺ carboxamide 3.57-3.64 (m, 2H),3.49-3.52 (m, 1H), 3.33 (s, 1.5H), 3.13 (s, 1.5H), 3.09 (s, 1.5H), 3.04(s, 1.5H). Example N-[(3R)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.88 (d, MS393 tetrahydrofuran-3-yl]- J = 7.0 Hz, 1H), 8.61-8.62 (m, 1H), 8.54 (d,(ESI) 6-{[5- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.24 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 8.6 Hz,1H), 404.1 2- 7.92 (d, J = 2.8 Hz, 1H), 7.76 (dd, J = 9.2, 2.8 Hz, [M +H]⁺ yl]oxy}quinoline-2- 1H), 7.40 (d, J = 8.5 Hz, 1H), 4.53-4.60 (m,carboxamide 1H), 3.85-3.96 (m, 2H), 3.69-3.79 (m, 2H), 2.20-2.28 (m,1H), 2.02-2.10 (m, 1H). Example N-[(2S)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.80 (t, MS 394 tetrahydrofuran-2- J = 6.1 Hz, 1H). 8.61-8.62 (m, 1H),8.54 (d, (ESI) ylmethyl]-6-{[5- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.5, 2.4Hz, 1H), m/z (trifluoromethyl)pyridin- 8.18-8.22 (m, 2H), 7.93 (d, J =2.4 Hz, 1H), 418.1 2- 7.76 (dd, J = 9.2, 2.4 Hz, 1H), 7.41 (d, J = 8.9Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H), 4.04-4.10 (m, 1H), 3.80-3.85 (m,1H), carboxamide 3.64-3.70 (m, 1H), 3.37-3.52 (m, 2H), 1.77-1.99 (m,3H), 1.59-1.69 (m, 1H). Example [(3R,5R)-3,5- ¹H NMR (400 MHz, DMSO-d₆)δ ppm ESI m/z 395 dihydroxypiperidin- 8.61-8.56 (m, 1H), 8.46 (d, J =8.5 Hz, 1H), 434.1 1-yl](6-{[5- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.09 (d,J = 9.0 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 7.88 (d, J = 2.6 Hz,1H), 7.74-7.62 (m, 2- 2H), 7.39 (d, J = 8.6 Hz, 1H), 4.93 (d, J = 4.2Hz, yl]oxy}quinolin-2- 1H), 4.72 (d, J = 3.5 Hz, 1H), 4.03 (dd, J =12.4, yl)methanone 3.8 Hz, 1H), 3.98-3.86 (m, 1H), 3.85-3.78 (m, 1H),3.38 (d, J = 3.9 Hz, 2H), 3.15 (dd, J = 12.2, 7.9 Hz, 1H), 1.86-1.76 (m,1H), 1.61 (m, 1H). Example (3-methoxyazetidin- ¹H NMR (500 MHz, DMSO-d₆)δ ppm ESI m/z 396 1-yl)(6-{[5- 8.62-8.58 (m, 1H), 8.49 (d, J = 8.5 Hz,1H), 404.1 (trifluoromethyl)pyridin- 8.31 (dd, J = 8.7, 2.6 Hz, 1H),8.17 (d, J = 9.1 Hz, [M + H]⁺ 2- 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.90 (d,J = 2.6 Hz, yl]oxy}quinolin-2- 1H), 7.73 (dd, J = 9.0, 2.6 Hz, 1H),yl)methanone 7.40 (d, J = 8.7 Hz, 1H), 4.96-4.89 (m, 1H), 4.55 (dd, J =11.0, 2.5 Hz, 1H), 4.36-4.27 (m, 2H), 4.07-3.90 (m, 1H), 3.27 (s, 3H).Example N-(trans-3- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.12 (d, ESI m/z 397methoxycyclobutyl)- J = 7.7 Hz, 1H), 8.64-8.59 (m, 1H), 8.52 (d, J = 8.5Hz, 418.1 6-{[5- 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), [M + H]⁺(trifluoromethyl)pyridin- 8.24 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 8.5 Hz,2- 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1, yl]oxy}quinoline-2-2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), carboxamide 4.63-4.51 (m, 1H),4.08-4.01 (m, 1H), 3.18 (s, 3H), 2.46-2.39 (m, 2H), 2.38-2.26 (m, 2H).Example N-(4-hydroxy-1,1- ¹H NMR (500 MHz, DMSO-d₆) δ ppm ESI m/z 398dioxidotetrahydrothiophen- 8.59 (bs, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.31(dd, J = 8.7, 482.0 3-yl)-N-methyl- 2.6 Hz, 1H), 8.13 (d, J = 7.9 Hz,1H), [M + H]⁺ 6-{[5- 7.90 (d, J = 2.6 Hz, 1H), 7.76-7.68 (m, 2H),(trifluoromethyl)pyridin- 7.40 (d, J = 8.7 Hz, 1H), 6.19-6.05 (m, 1H),5.17 2- and 4.73 (2m, 1H), 4.96 and 4.80 (2m, 1H), yl]oxy}quinoline-2-4.82-4.71 (m, 1H), 3.68-3.44 (m, 2H), carboxamide 3.27 (m, 1H), 3.16 and3.04 (2s, 3H). Example N-(oxetan-3-yl)-6- ¹H NMR (500 MHz, DMSO-d₆) δppm 9.58 (d, ESI m/z 399 {[5- J = 6.9 Hz, 1H), 8.64-8.59 (m, 1H), 8.54(d, J = 8.5 Hz, 390.1 (trifluoromethyl)pyridin- 1H), 8.32 (dd, J = 8.7,2.6 Hz, 1H), [M + H]⁺ 2- 8.25 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 8.4 Hz,yl]oxy}quinoline-2- 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.78 (dd, J = 9.1,carboxamide 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 5.11 (m, 1H),4.82-4.73 (m, 4H). Example N-(tetrahydro-2H- ¹H NMR (500 MHz, DMSO-d₆) δppm 8.79 (d, ESI m/z 400 thiopyran-4-yl)-6- J = 8.5 Hz, 1H), 8.64-8.59(m, 1H), 8.53 (d, J = 8.5 Hz, 434.1 {[5- 1H), 8.31 (dd, J = 8.6, 2.7 Hz,1H), [M + H]⁺ (trifluoromethyl)pyridin- 8.23 (d, J = 9.0 Hz, 1H), 8.16(d, J = 8.5 Hz, 2- 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.75 (dd, J = 9.1,yl]oxy}quinoline-2- 2.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), carboxamide3.96-3.85 (m, 1H), 2.82-2.73 (m, 2H), 2.72-2.64 (m, 2H), 2.17-2.09 (m,2H), 1.89-1.77 (m, 2H). Example N-[(1S,2R)-2- ¹H NMR (500 MHz, CDCl₃) δppm 8.50 (d, J = 7.8 Hz, MS 401 hydroxycyclopentyl]- 1H), 8.45 (d, J =0.5 Hz, 1H), (ESI) 6-{[5- 8.28 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.5 Hz,1H), m/z (trifluoromethyl)pyridin- 8.16 (d, J = 9.1 Hz, 1H), 7.97 (dd, J= 8.6, 2.5 Hz, 418.1 2- 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.57 (dd, J =9.1, [M + H]⁺ yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H),carboxamide 4.45-4.29 (m, 2H), 2.21-2.11 (m, 1H), 2.09-1.92 (m, 2H),1.88-1.78 (m, 2H), 1.73-1.63 (m, 1H). Example 4-[(6-{[5- ¹H NMR (400MHz, DMSO-d₆, rotamers) δ DCI m/z 402 (trifluoromethyl)pyridin- ppm2.55-3.02 (m, 3.5H), 3.06-3.28 (m, 446.0 2- 2H), 3.57 (d, J = 13.3 Hz,0.5H), 3.73 (dd, J = 12.8, [M + H]⁺ yl]oxy}quinolin-2- 2.9 Hz, 0.5H),3.95-4.14 (m, 1H), yl)carbonyl]piperazine- 4.50 (dd, J = 12.5, 3.0 Hz,0.5H), 7.11-7.26 (m, 2-carboxamide 1.56H), 7.39 (d, J = 8.6 Hz, 1.42H),7.64-7.76 (m, 2H), 7.89 (t, J = 2.3 Hz, 1H), 8.11 (dd, J = 9.1, 5.2 Hz,1H), 8.30 (dt, J = 8.7, 2.6 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.61 (t,J = 9.8 Hz, 1H) Example (4-aminopiperidin-1- ¹H NMR (400 MHz, DMSO-d₆) δppm DCI m/z 403 yl)(6-{[5- 1.19-1.41 (m, 2H), 1.66 (dd, J = 21.1, 7.3Hz, 1H), 417.0 (trifluoromethyl)pyridin- 1.83 (dd, J = 26.9, 17.6 Hz,1H), M + H]⁺ 2- 2.77-3.15 (m, 5H), 3.59-3.74 (m, 1H), 4.37 (d, J = 13.0Hz, yl]oxy}quinolin-2- 1H), 7.39 (d, J = 8.7 Hz, 1H), yl)methanone7.59-7.76 (m, 2H), 7.89 (d, J = 2.6 Hz, 1H), 8.11 (t, J = 7.6 Hz, 1H),8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.48 (dd, J = 8.3, 4.5 Hz, 1H), 8.59 (s,1H) Example (3,3- ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ MS 404difluoropyrrolidin-1- ppm 8.61-8.57 (m, 1H), 8.50 (dd, J = 8.5, 2.7 Hz,(ESI) yl)(6-{[5- 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.20 (d, J = 9.1 Hz, 0.5H), 8.16 (d, J = 9.1Hz, 424.1 2- 0.5H), 7.97 (d, J = 8.5 Hz, 0.5H), [M + H]⁺yl]oxy}quinolin-2- 7.92-7.89 (m, 1.5H), 7.74 (dd, J = 9.1, 2.6 Hz, 1H),yl)methanone 7.40 (d, J = 8.6 Hz, 1H), 4.40 (t, J = 13.1 Hz, 1H), 4.11(t, J = 7.4 Hz, 1H), 4.01 (t, J = 13.3 Hz, 1H), 3.83 (t, J = 7.6 Hz,1H), 2.57-2.45 (m, 2H). Example (3,3- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS405 dimethylpyrrolidin-1- 8.60-8.56 (m, 1H), 8.46 (d, J = 8.6 Hz, 1H),(ESI) yl)(6-{[5- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.13 (dd, J = 9.0, 7.3Hz, m/z (trifluoromethyl)pyridin- 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.84(dd, J = 9.6, 416.2 2- 8.6 Hz, 1H), 7.70 (dd, J = 9.1, 2.6 Hz, [M + H]⁺yl]oxy}quinolin-2- 1H), 7.39 (d, J = 8.7 Hz, 1H), 3.84 (t, J = 7.1 Hz,yl)methanone 1H), 3.65 (t, J = 7.2 Hz, 1H), 3.46 (s, 1H), 3.35 (s, 1H),1.75-1.68 (m, 2H), 1.13 (s, 3H), 1.03 (s, 3H). Example (6-fluoro-1,4- ¹HNMR (400 MHz, CDCl₃) δ ppm 8.45 (bs, MS 406 diazepan-1-yl)(6-{[5- 1H),8.24 (d, J = 8.6 Hz, 1H), 8.14 (dd, J = 9.1, (ESI)(trifluoromethyl)pyridin- 2.9 Hz, 1H), 7.99 (dd, J = 8.6, 2.5 Hz, 1H),m/z 2- 7.80 (dd, J = 14.7, 8.5 Hz, 1H), 7.64 (t, J = 2.2 Hz, 435.1yl]oxy}quinolin-2- 1H), 7.58 (dd, J = 9.1, 2.4 Hz, 1H), [M + H]⁺yl)methanone 7.16 (d, J = 8.6 Hz, 1H), 5.23-4.95 (m, 1H), 4.54-4.19 (m,1H), 4.17-3.71 (m, 2H), 3.64-2.95 (m, 6H). Example (6-hydroxy-1,4- ¹HNMR (400 MHz, CDCl₃) δ ppm 8.44 (s, MS 407 diazepan-1-yl)(6-{[5- 1H),8.26 (dd, J = 23.9, 8.6 Hz, 1H), 8.14 (d, J = 9.1 Hz, (ESI)(trifluoromethyl)pyridin- 1H), 7.99 (dd, J = 8.6, 2.5 Hz, 1H), m/z 2-7.86 (dd, J = 25.6, 8.5 Hz, 1H), 7.79-7.54 (m, 433.1 yl]oxy}quinolin-2-2H), 7.16 (dd, J = 8.6, 4.4 Hz, 1H), [M + H]⁺ yl)methanone 4.62-4.32 (m,2H), 4.31-4.11 (m, 2H), 3.87 (dddd, J = 25.4, 20.2, 14.4, 7.2 Hz, 1H),3.57-3.08 (m, 6H). Example N-{1-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆,rotamers) δ DCI m/z 408 (trifluoromethyl)pyridin- ppm 1.50 (td, J =14.4, 3.9 Hz, 2H), 1.84 (d, J = 10.1 Hz, 495.0 2- 1H), 2.00 (d, J = 9.3Hz, 1H), M + H]⁺ yl]oxy}quinolin-2- 2.95 (s, 3H), 2.99-3.13 (m, 1H),3.18 (dd, J = 24.1, yl)carbonyl]piperidin- 13.0 Hz, 1H), 3.40-3.59 (m,1H), 4- 3.71 (d, J = 13.8 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H),yl}methanesulfonamide 7.21 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 8.7 Hz,1H), 7.62-7.80 (m, 2H), 7.89 (d, J = 2.6 Hz, 1H), 8.10 (d, J = 9.1 Hz,1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.59 (s,1H) Example N-[(2R)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (t, MS 409tetrahydrofuran-2- J = 6.1 Hz, 1H). 8.61-8.62 (m, 1H), 8.54 (d, (ESI)ylmethyl]-6-{[5- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.5, 2.4 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.18-8.22 (m, 2H), 7.93 (d, J = 2.4 Hz, 1H),418.1 2- 7.76 (dd, J = 9.2, 2.4 Hz, 1H), 7.41 (d, J = 8.9 Hz, [M + H]⁺yl]oxy}quinoline-2- 1H), 4.04-4.10 (m, 1H), 3.80-3.85 (m, 1H),carboxamide 3.64-3.70 (m, 1H), 3.37-3.52 (m, 2H), 1.77-1.99 (m, 3H),1.59-1.69 (m, 1H). Example N-[(2S)-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.76 (t, MS 410 hydroxypropyl]-6- J = 6.0 Hz, 1H). 8.61-8.62 (m, 1H),8.55 (d, (ESI) {[5- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.18-8.22 (m, 2H), 7.93 (d, J = 2.8 Hz, 1H),392.1 2- 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.41 (d, J = 8.9 Hz, [M + H]⁺yl]oxy}quinoline-2- 1H), 4.91 (br s, 1H), 3.83-3.91 (m, 1H), carboxamide3.40-3.47 (m, 1H), 3.23-3.30 (m, 1H), 1.12 (d, J = 6.1 Hz, 3H). ExampleN-methyl-N- ¹H NMR (400 MHz, DMSO-d₆) 1:1 rotamers δ MS 411(tetrahydro-2H- ppm 8.59-8.60 (m, 1H), 8.46-8.49 (m, 1H), (ESI)pyran-4-yl)-6-{[5- 8.29-8.32 (m, 1H), 8.13 (d, J = 9.2 Hz, 0.5H), m/z(trifluoromethyl)pyridin- 8.07 (d, J = 9.2 Hz, 0.5H), 7.88-7.90 (m, 1H),417.1 2- 7.65-7.73 (m, 2H), 7.38-7.41 (m, 1H), [M + H]⁺yl]oxy}quinoline-2- 4.61-4.69 (m, 0.5H), 3.96-4.00 (m, 1H), carboxamide3.79-3.86 (m, 1.5H), 3.45-3.50 (m, 1H), 3.05-3.11 (m, 1H), 2.97 (s,1.5H), 2.86 (s, 1.5H), 1.63-1.95 (m, 4H). Example N-[(3-hydroxyoxetan-¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.91 (t, MS 412 3-yl)methyl]-6-{[5- J =6.3 Hz, 1H), 8.61-8.62 (m, 1H), 8.56 (d, (ESI) (trifluoromethyl)pyridin-J = 8.5 Hz, 1H), 8.32 (dd, J = 8.9, 2.4 Hz, 1H), m/z 2- 8.21-8.23 (m,2H), 7.94 (d, J = 2.4 Hz, 1H), 420.1 yl]oxy}quinoline-2- 7.77 (dd, J =9.2, 2.8 Hz, 1H), 7.41 (d, J = 8.5 Hz, [M + H]⁺ carboxamide 1H), 6.10(br s, 1H), 4.50 (d, J = 6.7 Hz, 2H), 4.45 (d, J = 6.4 Hz, 2H), 3.74 (d,J = 6.4 Hz, 2H). Example N-[2- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.45 (bs,MS 413 (dimethylamino)-2- 1H), 8.28-8.04 (m, 2H), 8.04-7.77 (m, 2H),(ESI) oxoethyl]-N-methyl- 7.68-7.51 (m, 2H), 7.15 (dd, J = 8.6, 5.3 Hz,m/z 6-{[5- 1H), 4.51 (d, J = 82.7 Hz, 2H), 3.25 (d, J = 8.6 Hz, 433.1(trifluoromethyl)pyridin- 3H), 2.99 (dd, J = 66.7, 25.6 Hz, 6H). [M +H]⁺ 2- yl]oxy}quinoline-2- carboxamide Example (6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm MS 414 (trifluoromethyl)pyridin- 8.60-8.56 (m, 1H), 8.49(dd, J = 8.5, 2.9 Hz, 1H), (ESI) 2- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.14(dd, J = 9.1, m/z yl]oxy}quinolin-2- 3.3 Hz, 1H), 7.92-7.87 (m, 2H),7.72 (dd, 456.1 yl)[3- J = 9.1, 2.6 Hz, 1H), 7.39 (dd, J = 8.6, 0.4 Hz,[M + H]⁺ (trifluoromethyl)pyrrolidin- 1H), 4.14 (dd, J = 12.0, 8.1 Hz,0.5H), 1- 4.00-3.86 (m, 2H), 3.82-3.74 (m, 0.5H), yl]methanone 3.72-3.61(m, 1H), 3.42-3.32 (m, 1H), 2.30-2.19 (m, 1H), 2.12-2.00 (m, 1H).Example (3,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 415difluoropyrrolidin-1- 8.61-8.58 (m, 1H), 8.50 (d, J = 8.4 Hz, 1H), (ESI)yl)(6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.18 (d, J = 9.1 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.91 (d, J =2.6 Hz, 424.1 2- 1H), 7.74 (dd, J = 9.1, 2.6 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 5.56-5.25 (m, 2H),yl)methanone 4.38-4.24 (m, 1H), 4.18-3.92 (m, 2H), 3.85-3.71 (m, 1H).Example N-(6-oxopiperidin-3- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.84 (d, MS416 yl)-6-{[5- J = 8.0 Hz, 1H), 8.62-8.59 (m, 1H), 8.54 (d, J = 8.6 Hz,(ESI) (trifluoromethyl)pyridin- 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), m/z2- 8.23 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 8.5 Hz, 431.1yl]oxy}quinoline-2- 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1,[M + H]⁺ carboxamide 2.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.40 (d, J = 8.7Hz, 1H), 4.31-4.22 (m, 1H), 3.41-3.24 (m, 2H), 2.38-2.27 (m, 2H),2.11-1.93 (m, 2H). Example (6,6-difluoro-1,4- ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.59 (s, MS 417 diazepan-1-yl)(6-{[5- 1H), 8.50 (dd, J = 8.5, 2.8Hz, 1H), 8.31 (dd, J = 8.7, (ESI) (trifluoromethyl)pyridin- 2.5 Hz, 1H),8.12 (d, J = 9.1 Hz, 1H), m/z 2- 7.90 (d, J = 2.5 Hz, 1H), 7.78-7.68 (m,2H), 453.1 yl]oxy}quinolin-2- 7.40 (dd, J = 8.7, 3.1 Hz, 1H), 4.30 (t, J= 12.9 Hz, [M + H]⁺ yl)methanone 1H), 4.20 (t, J = 13.1 Hz, 1H), 3.78(t, J = 5.0 Hz, 1H), 3.49 (t, J = 4.8 Hz, 1H), 3.24-3.12 (m, 1H), 3.04(dd, J = 25.5, 11.4 Hz, 1H), 2.87 (s, 1H), 1.34-1.07 (m, 1H), 0.89-0.80(m, 1H). Example 5,8- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS 418diazaspiro[3.5]non-8- 8.62-8.57 (m, 1H), 8.48 (dd, J = 11.0, 8.5 Hz,1H), (ESI) yl(6-{[5- 8.31 (ddd, J = 8.6, 2.6, 2.6 Hz, 1H), 8.09 (dd, J =14.7, m/z (trifluoromethyl)pyridin- 9.1 Hz, 1H), 7.90 (dd, J = 8.1, 2.6Hz, 443.1 2- 1H), 7.77-7.64 (m, 2H), 7.40 (dd, J = 13.4, [M + H]⁺yl]oxy}quinolin-2- 5.2 Hz, 1H) 3.63 (s, 1H), 3.62-3.55 (m, 1H),yl)methanone 3.36-3.31 (m, 2H), 2.75-2.73 (m, 1H), 2.65-2.58 (m, 1H),2.04-1.92 (m, 2H), 1.87-1.57 (m, 4H), 1.42-1.29 (m, 1H) Example N-(1,1-¹H NMR (500 MHz, DMSO-d₆) 0.7:0.3 MS 419 dioxidotetrahydrothiophen-rotamers δ ppm 8.59-8.60 (m, 1H), (ESI) 3-yl)-N-methyl- 8.49-8.51 (m,1H), 8.30-8.32 (m, 1H), 8.13-8.16 (m, 1H), m/z 6-{[5- 7.90-7.91 (m, 1H),7.71-7.76 (m, 2H), 466.1 (trifluoromethyl)pyridin- 7.39-7.41 (m, 1H),5.30-5.37 (m, 0.3H), [M + H]⁺ 2- 4.81-4.88 (m, 0.7H), 3.36-3.53 (m,2.3H), 3.24-3.29 (m, yl]oxy}quinoline-2- 1H), 3.04-3.08 (m, 0.7H), 3.02(m, 2.1H), carboxamide 2.97 (m, 0.9H), 2.30-2.46 (m, 2H). Example N- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.85 (d, MS 420 (tetrahydrothiophen- J =7.6 Hz, 1H), 8.61-8.62 (m, 1H), 8.54 (d, (ESI) 3-yl)-6-{[5- J = 8.5 Hz,1H), 8.32 (dd, J = 8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.23(d, J = 9.2 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 420.1 2- 7.93 (d, J = 2.4Hz, 1H), 7.76 (dd, J = 9.2, 2.8 Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H),7.41 (d, J = 8.9 Hz, 1H), 4.59-4.65 (m, carboxamide 1H), 3.05-3.08 (m,1H), 3.89-3.94 (m, 3H), 2.16-2.20 (m, 2H). Example N-[2-(2- ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.99 (t, MS 421 oxoimidazolidin-1- J = 6.1 Hz, 1H),8.60-8.61 (m, 1H), 8.53 (d, (ESI) yl)ethyl]-6-{[5- J = 8.5 Hz, 1H), 8.31(dd, J = 8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.16-8.19 (m,2H), 7.93 (d, J = 2.8 Hz, 1H), 446.1 2- 7.76 (dd, J = 9.0, 2.6 Hz, 1H),7.40 (d, J = 8.9 Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H), 6.28 (s, 1H),3.42-3.52 (m, 4H), carboxamide 3.29-3.33 (m, 2H), 3.20-3.24 (m, 2H).Example N-[2-(pyridin-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (t, MS 422ylamino)ethyl]-6-{[5- J = 5.5 Hz, 1H), 8.60-8.61 (m, 1H), 8.53 (d, (ESI)(trifluoromethyl)pyridin- J = 8.6 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz,1H), m/z 2- 8.17-8.20 (m, 2H), 8.04 (d, J = 4.9H z, 1H), 454.1yl]oxy}quinoline-2- 7.92 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 9.0, 2.6 Hz,[M + H]⁺ carboxamide 1H), 7.36-7.42 (m, 2H), 6.74 (t, J = 5.2 Hz, 1H),6.48-6.52 (m, 2H), 3.49-3.58 (m, 4H). Example N-[2-(1H-imidazol-1- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.05 (t, MS 423 yl)ethyl]-6-{[5- J = 6.0Hz, 1H), 8.60-8.61 (m, 1H), 8.54 (d, (ESI) (trifluoromethyl)pyridin- J =8.5 Hz, 1H), 8.31 (dd, J = 8.9, 2.4 Hz, 1H), m/z 2- 8.14-8.19 (m, 2H),7.93 (d, J = 2.4 Hz, 1H), 428.1 yl]oxy}quinoline-2- 7.76 (dd, J = 9.2,2.4 Hz, 1H), 7.62 (s, 1H), [M + H]⁺ carboxamide 7.41 (d, J = 8.5 Hz,1H), 7.19 (s, 1H), 6.87 (s, 1H), 4.26 (t, J = 6.3 Hz, 1H), 3.72 (q, J =6.1 Hz, 2H). Example N-(azetidin-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.30(t, MS 424 ylmethyl)-6-{[5- J = 6.1 Hz, 1H), 8.60-8.61 (m, 1H), 8.57 (d,(ESI) (trifluoromethyl)pyridin- J = 8.5 Hz, 1H), 8.33 (dd, J = 8.9, 2.4Hz, 1H), m/z 2- 8.19-8.22 (m, 2H), 7.96 (d, J = 2.8 Hz, 1H), 403.1yl]oxy}quinoline-2- 7.79 (dd, J = 9.2, 2.8 Hz, 1H), 7.42 (d, J = 8.5 Hz,[M + H]⁺ carboxamide 1H), 4.57-4.64 (m, 1H),), 3.72-3.95 (m, 4H),2.31-2.48 (m, 2H). Example N-[(3R,4R)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.88 (d, ESI m/z 425 hydroxy-1,1- J = 8.1 Hz, 1H), 8.62 (d, J = 3.0 Hz,1H), 468.0 dioxidotetrahydrothiophen- 8.58 (d, J = 8.5 Hz, 1H), 8.32(dd, J = 8.7, 2.6 Hz, [M + H]⁺ 3-yl]-6-{[5- 1H), 8.25-8.19 (m, 2H), 7.95(d, J = 2.6 Hz, (trifluoromethyl)pyridin- 1H), 7.78 (dd, J = 9.1, 2.7Hz, 1H), 7.41 (d, J = 8.6 Hz, 2- 1H), 6.29 (s, 1H), 4.86-4.75 (m, 1H),yl]oxy}quinoline-2- 4.66-4.60 (m, 1H), 3.61-3.27 (m, 4H). carboxamideExample N-(3-hydroxy-3- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.86 (d, ESI m/z426 methylcyclobutyl)-6- J = 7.8 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H),418.0 {[5- 8.52 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.14 (d, J =8.4 Hz, 2- 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.0,yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), carboxamide5.00 (s, 1H), 4.13-3.99 (m, 1H), 2.42-2.33 (m, 2H), 2.27-2.20 (m, 2H),1.29 (s, 3H). Example [3-(2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESI m/z 427methoxyethoxy)azetidin- 8.63 (bs, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.14(dd, J = 8.7, 448.0 1-yl](6-{[5- 2.6 Hz, 1H), 8.04-7.96 (m, 2H), [M +H]⁺ (trifluoromethyl)pyridin- 7.51-7.43 (m, 2H), 7.15 (d, J = 8.7 Hz,1H), 2- 5.59-5.50 (m, 1H), 5.22-5.14 (m, 1H), yl]oxy}quinolin-2-4.79-4.70 (m, 1H), 4.62-4.54 (m, 1H), 4.30-4.24 (m, yl)methanone 2H),4.18-4.10 (m, 1H), 3.78-3.71 (m, 2H). Example N-{1-[(6-{[5- ¹H NMR (400MHz, DMSO-d₆) δ ppm ESI m/z 428 (trifluoromethyl)pyridin- 8.62-8.57 (m,1H), 8.50 (d, J = 8.5 Hz, 1H), 467.1 2- 8.31 (dd, J = 8.7, 2.6 Hz, 1H),8.17 (d, J = 9.0 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 8.07 (d, J = 8.5Hz, 1H), 7.96-7.88 (m, yl)carbonyl]azetidin- 2H), 7.74 (dd, J = 9.0, 2.7Hz, 1H), 7.40 (d, J = 8.6 Hz, 3- 1H), 5.07 (dd, J = 10.7, 7.8 Hz, 1H),yl}methanesulfonamide 4.62 (dd, J = 10.8, 5.4 Hz, 1H), 4.50-4.42 (m,1H), 4.38-4.27 (m, 1H), 4.03 (dd, J = 10.5, 5.2 Hz, 1H), 2.95 (s, 3H).Example (6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.47 (d, MS 429(difluoromethyl)pyridin- J = 8.6 Hz, 1H), 8.42-8.36 (m, 1H), 8.16 (d, J= 9.1 Hz, (ESI) 2-yl]oxy}quinolin- 1H), 8.13 (dd, J = 8.6, 2.2 Hz, 1H),m/z 2-yl)[3-(morpholin-4- 8.03 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 2.6 Hz,441.1 yl)azetidin-1- 1H), 7.69 (dd, J = 9.1, 2.6 Hz, 1H), 7.32 (d, J =8.6 Hz, [M + H]⁺ yl]methanone 1H), 7.12 (t, J = 55.3 Hz, 1H), 4.76 (dd,J = 10.2, 7.2 Hz, 1H), 4.55 (dd, J = 10.6, 4.8 Hz, 1H), 4.15 (dd, J =10.1, 7.4 Hz, 1H), 3.96 (dd, J = 10.5, 4.8 Hz, 1H), 3.65-3.56 (m, 4H),3.23-3.15 (m, 1H), 2.37 (br s, 4H). Example [2- ¹H NMR (400 MHz,DMSO-d₆, rotamers) δ MS 430 (difluoromethyl)piperazin- ppm 8.49 (d, J =8.5 Hz, 1H), 8.41-8.36 (m, (ESI) 1-yl](6-{[5- 1H), 8.17-8.07 (m, 2H),7.86 (d, J = 2.6 Hz, m/z (difluoromethyl)pyridin- 1H), 7.75-7.63 (m,2H), 7.32 (d, J = 8.6 Hz, 435.1 2-yl]oxy}quinolin- 1H), 7.12 (t, J =55.3 Hz, 1H), 6.55 (tdd, J = 57.1, [M + H]⁺ 2-yl)methanone 29.3, 6.7 Hz,1H), 4.84-4.72 (m, 0.5H), 4.44-4.26 (m, 1H), 3.57 (d, J = 13.1 Hz,0.5H), 3.38-3.34 (m, 0.5H), 3.16 (d, J = 13.2 Hz, 0.5H), 3.12-2.92 (m,2H), 2.89-2.53 (m, 3H). Example piperazin-1-yl(6-{[5- 1H NMR (300 MHz,DMSO-d6): 8.46 (d, (APCI) 431 (trifluoromethoxy)pyridin- J = 8.5 Hz,1H), 8.29 (d, J = 2.8 Hz, 1H), 8.09 (d, m/z 2- J = 9.2 Hz, 1H), 8.03(dd, J = 8.7, 2.6 Hz, 1H), 418.9 yl]oxy}quinolin-2- 7.83 (d, J = 2.8 Hz,1H), 7.65-7.69 (m, 2H), [M + H]+ yl)methanone 7.33 (d, J = 8.9 Hz, 1H),3.62-3.65 (m, 2H), 3.37-3.40 (m, 2H), 2.79-2.82 (m, 2H), 2.67-3.69 (m,2H). Example N-(3-oxocyclobutyl)- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.42(t, DCI m/z 432 6-{[5- J = 8.0 Hz, 4H), 4.64-4.78 (m, 1H), 7.41 (d, J =8.7 Hz, 402.0 (trifluoromethyl)pyridin- 1H), 7.77 (dd, J = 9.1, 2.6 Hz,1H), M + H]⁺ 2- 7.94 (d, J = 2.6 Hz, 1H), 8.20 (dd, J = 21.7, 8.8 Hz,yl]oxy}quinoline-2- 2H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), carboxamide8.54 (d, J = 8.5 Hz, 1H), 8.59-8.65 (m, 1H), 9.52 (d, J = 7.6 Hz, 1H)Example N-[3-(morpholin-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 433yl)cyclobutyl]-6-{[5- 2.06 (qd, J = 8.8, 2.4 Hz, 2H), 2.30 (s, 4H),473.0 (trifluoromethyl)pyridin- 2.37-2.46 (m, 2H), 3.54-3.64 (m, 4H),M + H]⁺ 2- 4.16-4.33 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.76 (dd, J =9.1, yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H),carboxamide 8.13 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.31(dd, J = 8.7, 2.5 Hz, 1H), 8.52 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 1.5Hz, 1H), 9.03 (d, J = 8.3 Hz, 1H) Example 6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.17 (d, DCI m/z 434 (difluoromethyl)pyridin- J = 6.1 Hz,7H), 3.37 (d, J = 6.2 Hz, 2H), 388.0 2-yl]oxy}-N-(2- 4.76 (s, 1H), 7.13(t, J = 55.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, M + H]⁺ hydroxy-2- 1H), 7.73(dd, J = 9.1, 2.6 Hz, 1H), methylpropyl)quinoline- 7.90 (d, J = 2.6 Hz,1H), 8.17 (ddd, J = 10.6, 2-carboxamide 8.9, 2.8 Hz, 3H), 8.41 (d, J =1.3 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.63 (t, J = 6.1 Hz, 1H) Example(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 435(difluoromethyl)pyridin- 1.44 (qd, J = 12.2, 4.2 Hz, 2H), 1.73 (d, J =12.2 Hz, 469.0 2-yl]oxy}quinolin- 1H), 1.92 (d, J = 12.3 Hz, 1H),2.48-2.56 (m, M + H]⁺ 2-yl)[4-(morpholin-4- 5H), 2.90 (td, J = 12.7, 2.6Hz, 1H), 3.09 (t, J = 11.5 Hz, yl)piperidin-1- 1H), 3.50-3.64 (m, 4H),3.74 (d, J = 13.4 Hz, yl]methanone 1H), 4.53 (d, J = 13.2 Hz, 1H), 7.12(t, J = 55.3 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 8.7, 3.6Hz, 2H), 7.84 (d, J = 2.6 Hz, 1H), 8.05-8.18 (m, 2H), 8.39 (d, J = 1.5Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H). Example 6-{[5- ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.46 (t, 436 (difluoromethyl)pyridin- J = 6.6 Hz, 1H),8.57 (d, J = 8.6 Hz, 1H), 2-yl]oxy}-N- 8.43-8.39 (m, 1H), 8.22 (d, J =9.1 Hz, 1H), (2,2,2- 8.19 (d, J = 8.5 Hz, 1H), 8.14 (dd, J = 8.5, 2.3Hz, trifluoroethyl)quinoline- 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.76 (dd, J= 9.2, 2-carboxamide 2.7 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.13 (t, J =55.3 Hz, 1H), 4.23-4.10 (m, 2H). Example N-(4,4- ¹H NMR (500 MHz,DMSO-d₆) δ ppm DCI m/z 437 difluorocyclohexyl)- 1.69-2.18 (m, 8H),3.97-4.14 (m, 1H), 7.13 (t, J = 55.3 Hz, 434.0 6-{[5- 1H), 7.33 (d, J =8.6 Hz, 1H), M + H]⁺ (difluoromethyl)pyridin- 7.73 (dd, J = 9.1, 2.7 Hz,1H), 7.88 (d, J = 2.6 Hz, 2- 1H), 8.14 (dd, J = 12.4, 5.4 Hz, 2H), 8.21(d, J = 9.1 Hz, yl]oxy}quinoline-2- 1H), 8.41 (d, J = 1.4 Hz, 1H),carboxamide 8.52 (d, J = 8.5 Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H) ExampleN-{(3R)-1-[(6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.59 (s, MS 438(trifluoromethyl)pyridin- 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.34-8.27 (m,(ESI) 2- 1H), 8.22-8.11 (m, 2H), 7.90-7.86 (m, 2H), m/zyl]oxy}quinolin-2- 7.72 (dd, J = 9.1, 2.6 Hz, 1H), 7.39 (d, J = 8.7 Hz,445.1 yl)carbonyl]pyrrolidin- 1H), 4.33-4.21 (m, 1H), 4.01-3.43 (m, 4H),[M + H]⁺ 3-yl}acetamide 2.16-2.06 (m, 1H), 1.88-1.78 (m, 4H) ExampleN-{(3R)-1-[(6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.60 (s, MS 439(trifluoromethyl)pyridin- 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.45-8.35 (m,(ESI) 2- 1H), 8.31 (dd, J = 8.7, 2.8, 2.8 Hz, 1H), m/zyl]oxy}quinolin-2- 8.13 (dd, J = 12.7, 9.1 Hz, 1H), 7.92-7.85 (m, 471.1yl)carbonyl]pyrrolidin- 2H), 7.72 (ddd, J = 9.1, 2.5, 2.5 Hz, 1H), [M +H]⁺ 3- 7.40 (dd, J = 8.7, 2.6 Hz, 1H), 4.41-4.21 (m, 1H),yl}cyclopropanecarboxamide 4.03-3.42 (m, 4H), 2.23-2.04 (m, 1H),1.95-1.80 (m, 1H), 1.67-1.46 (m, 1H), 0.80-0.52 (m, 4H) Example (6-{[5-¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 440 (difluoromethyl)pyridin-2.66-3.06 (m, 4H), 3.07-3.29 (m, 3H), 3.76 (d, J = 13.7 Hz, 415.02-yl]oxy}quinolin- 0.5H), 3.83 (t, J = 12.4 Hz, 0.5H), M + H]⁺2-yl)[(3R)-3- 4.43 (d, J = 12.9 Hz, 0.5H), 4.54 (d, J = 12.8 Hz,(hydroxymethyl)piperazin- 0.5H), 4.91 (d, J = 88.7 Hz, 1H), 7.12 (t, J =55.3 Hz, 1-yl]methanone 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.63-7.77 (m,2H), 7.85 (d, J = 2.6 Hz, 1H), 8.04-8.19 (m, 2H), 8.39 (s, 1H), 8.49 (t,J = 8.2 Hz, 1H) Example 6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.94 (t,MS 441 (difluoromethyl)pyridin- J = 5.1 Hz, 1H), 8.56 (d, J = 8.6 Hz,1H), (ESI) 2-yl]oxy}-N-[2- 8.43 (t, J = 8.6 Hz, 1H), 8.19 (dd, J = 8.8,1.7 Hz, m/z (dimethylamino)-2- 2H), 8.13 (dt, J = 8.2, 4.1 Hz, 1H), 7.90(d, J = 2.6 Hz, 401.0 oxoethyl]quinoline-2- 1H), 7.74 (dd, J = 9.1, 2.6Hz, 1H), [M + H]⁺ carboxamide 7.34 (d, J = 8.6 Hz, 1H), 7.13 (t, J =55.3 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 3.04 (s, 3H), 2.91 (s, 3H).Example N-{2-[(2- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 442methoxyethyl)amino] 8.55 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.25 (dd,(ESI) 2-oxoethyl}-N- J = 8.7, 2.5 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), m/zmethyl-6-{[5- 7.83 (d, J = 2.2 Hz, 1H), 7.77-7.64 (m, 2H), 463.3(trifluoromethyl)pyridin- 7.35 (d, J = 8.7 Hz, 1H), 4.20 (s, 2H), [M +H]⁺ 2- 3.46-3.18 (m, 7H), 3.10 (s, 3H). yl]oxy}quinoline-2- carboxamideExample N-[2-(morpholin-4- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 443yl)-2-oxoethyl]-6- 8.61-8.50 (m, 2H), 8.30-8.16 (m, 3H), (ESI) {[5- 7.89(d, J = 2.6 Hz, 1H), 7.75 (dd, J = 9.2, 2.7 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.37 (d, J = 8.7 Hz, 1H), 4.31 (s, 2H),461.2 2- 3.71-3.61 (m, 4H), 3.59-3.51 (m, 4H). [M + H]⁺yl]oxy}quinoline-2- carboxamide Example N-[3-(morpholin-4- ¹H NMR (400MHz, DMSO-d₆/D₂O) δ ppm MS 444 yl)-3-oxopropyl]-6- 8.57 (s, 1H), 8.51(t, J = 9.6 Hz, 1H), 8.25 (dd, (ESI) {[5- J = 8.7, 2.6 Hz, 1H), 8.20(dd, J = 12.8, 8.9 Hz, m/z (trifluoromethyl)pyridin- 2H), 7.86 (t, J =6.6 Hz, 1H), 7.73 (dd, J = 9.1, 475.3 2- 2.6 Hz, 1H), 7.36 (d, J = 8.7Hz, 1H), [M + H]⁺ yl]oxy}quinoline-2- 3.68 (t, J = 6.8 Hz, 2H),3.64-3.57 (m, 4H), carboxamide 3.55-3.47 (m, 4H), 2.72 (t, J = 6.7 Hz,2H). Example N-[3-oxo-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 445(pyrrolidin-1- 8.59-8.50 (m, 2H), 8.29-8.15 (m, 3H), (ESI)yl)propyl]-6-{[5- 7.87 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.6 Hz,m/z (trifluoromethyl)pyridin- 1H), 7.36 (d, J = 8.6 Hz, 1H), 3.67 (t, J= 6.7 Hz, 459.3 2- 2H), 3.41 (dt, J = 35.1, 6.7 Hz, 4H), [M + H]⁺yl]oxy}quinoline-2- 2.65 (t, J = 6.7 Hz, 2H), 1.86 (dt, J = 13.2, 7.0Hz, carboxamide 4H). Example N-[2-(diethylamino)- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 446 2-oxoethyl]-6-{[5- 8.62-8.49 (m, 2H),8.31-8.16 (m, 3H), (ESI) (trifluoromethyl)pyridin- 7.88 (d, J = 2.6 Hz,1H), 7.75 (dd, J = 9.1, 2.6 Hz, m/z 2- 1H), 7.37 (d, J = 8.7 Hz, 1H),4.28 (s, 2H), 447.2 yl]oxy}quinoline-2- 3.41 (q, J = 7.1 Hz, 4H), 1.18(s, 6H). [M + H]⁺ carboxamide Example N-[2-oxo-2- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 447 (piperidin-1- 8.62-8.49 (m, 2H), 8.31-8.16 (m,3H), (ESI) yl)ethyl]-6-{[5- 7.88 (d, J = 2.6 Hz, 1H), 7.75 (dd, J = 9.1,2.6 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.37 (d, J = 8.6 Hz, 1H),4.28 (s, 2H), 459.3 2- 3.51 (d, J = 5.4 Hz, 4H), 1.65 (d, J = 4.6 Hz,[M + H]⁺ yl]oxy}quinoline-2- 2H), 1.57 (s, 4H). carboxamide ExampleN-(1-methyl-5- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 448oxopyrrolidin-3-yl)- 8.29 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.98 (d,(ESI) 6-{[5- J = 9.3 Hz, 2H), 7.89 (d, J = 8.5 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.60 (d, J = 2.6 Hz, 1H), 7.46 (dd, J = 9.2,2.6 Hz, 431.2 2- 1H), 7.09 (d, J = 8.7 Hz, 1H), 4.41 (ddd, J = 13.4,[M + H]⁺ yl]oxy}quinoline-2- 8.2, 5.2 Hz, 1H), 3.52 (dd, J = 10.2, 7.7Hz, carboxamide 1H), 3.20 (dd, J = 10.2, 4.8 Hz, 1H), 2.54 (s, 3H), 2.47(dd, J = 17.0, 8.8 Hz, 1H), 2.33-2.20 (m, 1H). Example N-[3-oxo-3- ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 449 (piperidin-1- 8.56 (s, 1H), 8.52(d, J = 8.5 Hz, 1H), 8.25 (dd, (ESI) yl)propyl]-6-{[5- J = 8.7, 2.5 Hz,1H), 8.20 (dd, J = 12.1, 8.8 Hz, m/z (trifluoromethyl)pyridin- 2H), 7.87(d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 473.3 2- 2.6 Hz, 1H), 7.36 (d, J= 8.6 Hz, 1H), [M + H]⁺ yl]oxy}quinoline-2- 3.66 (t, J = 6.8 Hz, 2H),3.54-3.41 (m, 4H), carboxamide 2.70 (t, J = 6.8 Hz, 2H), 1.67-1.56 (m,2H), 1.51 (s, 4H). Example 1-methyl-4-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 450 (trifluoromethyl)pyridin- 8.59-8.51 (m, 1H),8.50-8.44 (m, 1H), (ESI) 2- 8.28-8.19 (m, 1H), 8.17-8.10 (m, 1H), m/zyl]oxy}quinolin-2- 7.86-7.81 (m, 1H), 7.79-7.74 (m, 1H), 431.2yl)carbonyl]piperazin- 7.73-7.65 (m, 1H), 7.38-7.30 (m, 1H), 4.27 (s,2H), [M + H]⁺ 2-one 3.99-3.80 (m, 2H), 3.52-3.41 (m, 2H), 2.92 (s, 3H).Example N,N-dimethyl-1-[(6- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 451{[5- 8.54 (s, 1H), 8.48-8.34 (m, 1H), 8.23 (dd, J = 8.7, (ESI)(trifluoromethyl)pyridin- 2.5 Hz, 1H), 8.18-7.98 (m, 1H), m/z 2-7.91-7.76 (m, 2H), 7.68 (dd, J = 9.1, 2.5 Hz, 1H), 459.3yl]oxy}quinolin-2- 7.32 (d, J = 8.7 Hz, 1H), 5.66-4.99 (m, 1H), [M + H]⁺yl)carbonyl]-L- 3.94-3.68 (m, 2H), 2.74 (d, J = 130.6 Hz, prolinamide6H), 2.46-2.22 (m, 1H), 2.07-1.75 (m, 3H). Example N-[2- ¹H NMR (400MHz, DMSO-d₆/D₂O) δ ppm MS 452 (cyclopropylamino)- 8.54-8.50 (m, 1H),8.41 (d, J = 8.5 Hz, 1H), (ESI) 2-oxoethyl]-N- 8.19 (dd, J = 8.6, 2.6Hz, 1H), 8.08 (d, J = 9.1 Hz, m/z methyl-6-{[5- 1H), 7.78 (d, J = 2.6Hz, 1H), 445.2 (trifluoromethyl)pyridin- 7.73-7.63 (m, 2H), 7.30 (d, J =8.6 Hz, 1H), [M + H]⁺ 2- 4.17-4.12 (m, 2H), 3.08 (d, J = 4.1 Hz, 3H),2.64 (s, 1H), yl]oxy}quinoline-2- 0.66-0.59 (m, 2H), 0.55-0.33 (m, 2H).carboxamide Example N-[3-(diethylamino)- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δppm MS 453 3-oxopropyl]-6-{[5- 8.54 (d, J = 0.8 Hz, 1H), 8.51 (dd, J =8.4, 4.2 Hz, (ESI) (trifluoromethyl)pyridin- 1H), 8.28-8.21 (m, 1H),8.20-8.13 (m, m/z 2- 2H), 7.84 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 9.1,461.3 yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.37-7.31 (m, 1H), 3.65 (t, J =6.8 Hz, [M + H]⁺ carboxamide 2H), 3.33 (dt, J = 9.1, 4.5 Hz, 4H), 2.67(t, J = 6.8 Hz, 2H), 1.23-0.95 (m, 6H). Example N-[2- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 454 (isopropylamino)-2- 8.56-8.50 (m, 1H),8.49-8.35 (m, 1H), (ESI) oxoethyl]-N-methyl- 8.26-8.17 (m, 1H),8.16-8.03 (m, 1H), m/z 6-{[5- 7.85-7.77 (m, 1H), 7.75-7.63 (m, 2H),447.3 (trifluoromethyl)pyridin- 7.38-7.29 (m, 1H), 4.12 (s, 2H),4.02-3.72 (m, 1H), [M + H]⁺ 2- 3.08 (d, J = 8.8 Hz, 3H), 1.27-0.88 (m,6H). yl]oxy}quinoline-2- carboxamide Example 1-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 455 (difluoromethyl)pyridin- 8.38 (s, 2H), 8.09(d, J = 8.4 Hz, 2H), 7.83 (d, (ESI) 2-yl]oxy}quinolin- J = 9.0 Hz, 1H),7.75 (s, 1H), 7.64 (d, J = 9.4 Hz, m/z 2-yl)carbonyl]-N- 1H), 7.26 (d, J= 8.5 Hz, 1H), 7.04 (t, J = 55.5 Hz, 427.2 methyl-L- 1H), 3.75 (s, 2H),2.66 (s, 1H), [M + H]⁺ prolinamide 2.42 (s, 2H), 2.21 (s, 1H), 2.02-1.80(m, 4H). Example 6-{[5- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 456(difluoromethyl)pyridin- 8.51 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.19(dd, (ESI) 2-yl]oxy}-N-[2- J = 14.5, 8.8 Hz, 2H), 8.10 (d, J = 8.5 Hz,1H), m/z oxo-2-(pyrrolidin-1- 7.82 (d, J = 2.6 Hz, 1H), 7.70 (dd, J =9.1, 2.6 Hz, 427.2 yl)ethyl]quinoline-2- 1H), 7.28 (d, J = 8.5 Hz, 1H),7.04 (t, J = 55.5 Hz, [M + H]⁺ carboxamide 1H), 4.19 (s, 2H), 3.56-3.34(m, 4H), 2.03-1.75 (m, 4H). Example 6-{[5- ¹H NMR (400 MHz, DMSO-d₆/D₂O)δ ppm MS 457 (difluoromethyl)pyridin- 8.42 (s, 1H), 8.37 (s, 1H), 8.08(d, J = 8.5 Hz, (ESI) 2-yl]oxy}-N-{2- 2H), 7.77 (s, 1H), 7.70 (d, J =8.5 Hz, 1H), m/z [(2- 7.65 (dd, J = 9.1, 2.5 Hz, 1H), 7.26 (d, J = 8.6Hz, 445.3 methoxyethyl)amino]- 1H), 7.04 (t, J = 55.5 Hz, 1H), 4.17 (s,[M + H]⁺ 2-oxoethyl}-N- 2H), 3.28 (s, 7H), 3.08 (s, 3H).methylquinoline-2- carboxamide Example 6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 458 (difluoromethyl)pyridin- 8.52 (d, J = 8.5 Hz,1H), 8.39 (s, 1H), 8.18 (dd, (ESI) 2-yl]oxy}-N-[2- J = 14.6, 8.8 Hz,2H), 8.10 (d, J = 8.8 Hz, 1H), m/z (morpholin-4-yl)-2- 7.82 (d, J = 2.6Hz, 1H), 7.70 (dd, J = 9.2, 2.6 Hz, 443.2 oxoethyl]quinoline-2- 1H),7.28 (d, J = 8.5 Hz, 1H), 7.04 (t, J = 55.4 Hz, [M + H]⁺ carboxamide1H), 4.28 (s, 2H), 3.69-3.60 (m, 4H), 3.56-3.49 (m, 4H). Example 6-{[5-¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 459 (difluoromethyl)pyridin- 8.49(d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.16 (dd, (ESI) 2-yl]oxy}-N-[3- J =11.6, 8.9 Hz, 2H), 8.09 (d, J = 8.7 Hz, 1H), m/z (morpholin-4-yl)-3-7.80 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.1, 2.6 Hz, 457.3oxopropyl]quinoline- 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.04 (t, J = 55.6Hz, [M + H]⁺ 2-carboxamide 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.61-3.54 (m,4H), 3.53-3.44 (m, 4H), 2.69 (t, J = 6.7 Hz, 2H). Example 6-{[5- ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ ppm MS 460 (difluoromethyl)pyridin- 8.49 (d, J= 8.6 Hz, 1H), 8.38 (s, 1H), 8.16 (dd, (ESI) 2-yl]oxy}-N-[3- J = 12.6,8.8 Hz, 2H), 8.09 (d, J = 8.6 Hz, 1H), m/z oxo-3-(pyrrolidin-1- 7.80 (d,J = 2.6 Hz, 1H), 7.68 (dd, J = 9.1, 2.6 Hz, 441.3 yl)propyl]quinoline-1H), 7.27 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 55.5 Hz, [M + H]⁺2-carboxamide 1H), 3.64 (t, J = 6.7 Hz, 2H), 3.39 (dt, J = 34.8, 6.5 Hz,4H), 2.62 (t, J = 6.7 Hz, 2H), 1.83 (dt, J = 38.2, 6.6 Hz, 4H). ExampleN-[2-(diethylamino)- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 4612-oxoethyl]-6-{[5- 8.51 (d, J = 8.5 Hz, 1H), 8.39 (d, J = 1.4 Hz, (ESI)(difluoromethyl)pyridin- 1H), 8.19 (dd, J = 14.0, 8.8 Hz, 2H), 8.09 (dd,m/z 2- J = 8.5, 2.3 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 429.2yl]oxy}quinoline-2- 7.70 (dd, J = 9.1, 2.7 Hz, 1H), 7.28 (d, J = 8.6 Hz,[M + H]⁺ carboxamide 1H), 7.04 (t, J = 55.5 Hz, 1H), 4.26 (s, 2H), 3.38(q, J = 7.1 Hz, 4H), 1.16 (s, 6H). Example 6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 462 (difluoromethyl)pyridin- 8.49 (d, J = 8.5 Hz,1H), 8.38 (s, 1H), 8.22 (d, (ESI) 2-yl]oxy}-N-(1- J = 9.2 Hz, 1H), 8.13(d, J = 8.5 Hz, 1H), m/z methyl-5- 8.10 (d, J = 8.6 Hz, 1H), 7.80 (d, J= 2.6 Hz, 1H), 413.2 oxopyrrolidin-3- 7.69 (dd, J = 9.2, 2.6 Hz, 1H),7.27 (d, J = 8.6 Hz, [M + H]⁺ yl)quinoline-2- 1H), 7.04 (t, J = 55.5 Hz,1H), 4.66 (ddd, J = 13.5, carboxamide 8.2, 5.4 Hz, 1H), 3.77 (dd, J =10.1, 7.7 Hz, 1H), 3.44 (dd, J = 10.2, 4.8 Hz, 1H), 2.79 (s, 3H), 2.71(dd, J = 17.0, 8.8 Hz, 1H), 2.56-2.47 (m, 1H). Example 6-{[5- ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ ppm MS 463 (difluoromethyl)pyridin- 8.49 (d, J= 8.5 Hz, 1H), 8.38 (s, 1H), 8.16 (dd, (ESI) 2-yl]oxy}-N-[3- J = 10.9,8.9 Hz, 2H), 8.09 (d, J = 8.7 Hz, 1H), m/z oxo-3-(piperidin-1- 7.80 (d,J = 2.6 Hz, 1H), 7.68 (dd, J = 9.2, 2.6 Hz, 455.3 yl)propyl]quinoline-1H), 7.27 (d, J = 8.5 Hz, 1H), 7.04 (t, J = 55.4 Hz, [M + H]⁺2-carboxamide 1H), 3.64 (t, J = 6.8 Hz, 2H), 3.45 (d, J = 5.2 Hz, 4H),2.67 (t, J = 6.8 Hz, 2H), 1.58 (d, J = 4.5 Hz, 2H), 1.48 (s, 4H).Example 4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 464(difluoromethyl)pyridin- 8.47 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.11(dd, (ESI) 2-yl]oxy}quinolin- J = 15.5, 7.8 Hz, 2H), 7.79 (d, J = 2.6Hz, 1H), m/z 2-yl)carbonyl]-1- 7.75 (d, J = 8.5 Hz, 1H), 7.67 (dd, J =9.2, 2.6 Hz, 413.3 methylpiperazin-2- 1H), 7.27 (d, J = 8.5 Hz, 1H),7.04 (t, J = 55.5 Hz, [M + H]⁺ one 1H), 4.27 (s, 2H), 3.91 (s, 2H), 3.47(t, J = 5.5 Hz, 2H), 2.92 (s, 3H). Example 1-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 465 (difluoromethyl)pyridin- 8.48-8.32 (m, 2H),8.18-7.95 (m, 2H), (ESI) 2-yl]oxy}quinolin- 7.91-7.72 (m, 2H), 7.65 (d,J = 9.0 Hz, 1H), m/z 2-yl)carbonyl]-N,N- 7.26 (d, J = 8.5 Hz, 1H), 7.04(t, J = 55.4 Hz, 1H), 441.3 dimethyl-L- 5.66-4.97 (m, 1H), 3.95-3.82 (m,1H), [M + H]⁺ prolinamide 3.75 (d, J = 4.4 Hz, 1H), 2.72 (d, J = 145.7Hz, 8H), 1.91 (d, J = 6.5 Hz, 2H). Example N-[2- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 466 (cyclopropylamino)- 8.50-8.32 (m, 2H),8.18-7.98 (m, 2H), (ESI) 2-oxoethyl]-6-{[5- 7.77 (s, 1H), 7.73-7.59 (m,2H), 7.26 (d, J = 8.8 Hz, m/z (difluoromethyl)pyridin- 1H), 7.04 (t, J =55.4 Hz, 1H), 4.11 (s, 427.2 2-yl]oxy}-N- 2H), 3.07 (s, 3H), 2.68 (s,1H), 0.76-0.20 (m, [M + H]⁺ methylquinoline-2- 4H). carboxamide ExampleN-[3-(diethylamino)- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 4673-oxopropyl]-6-{[5- 8.49 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.16 (t, J =8.8 Hz, (ESI) (difluoromethyl)pyridin- 2H), 8.12-8.06 (m, 1H), 7.80 (d,J = 2.6 Hz, m/z 2- 1H), 7.68 (dd, J = 9.1, 2.6 Hz, 1H), 443.3yl]oxy}quinoline-2- 7.27 (d, J = 8.5 Hz, 1H), 7.04 (t, J = 55.5 Hz, [M +H]⁺ carboxamide 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.33 (q, J = 7.1 Hz, 4H),2.67 (t, J = 6.8 Hz, 2H), 1.09 (s, 6H). Example 6-{[5- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 468 (difluoromethyl)pyridin- 8.49-8.32 (m, 2H),8.15-8.00 (m, 2H), (ESI) 2-yl]oxy}-N-[2- 7.77 (s, 1H), 7.72-7.60 (m,2H), 7.26 (d, J = 8.5 Hz, m/z (isopropylamino)-2- 1H), 7.04 (t, J = 55.5Hz, 1H), 4.12 (s, 429.2 oxoethyl]-N- 2H), 4.00-3.70 (m, 1H), 3.07 (s,3H), 1.06 (d, [M + H]⁺ methylquinoline-2- J = 46.2 Hz, 6H). carboxamideExample N-[2-(2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.92 (t, MS 469oxopiperazin-1- J = 6.0 Hz, 1H), 8.61-8.62 (m, 1H), 8.54 (d, (ESI)yl)ethyl]-6-{[5- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.5, 2.4 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.17-8.20 (m, 2H), 7.93 (d, J = 2.4 Hz, 1H),460.1 2- 7.75-7.77 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), [M + H]⁺yl]oxy}quinoline-2- 3.52 (q, J = 6.4 Hz, 1H), 3.16-3.18 (m, 2H),carboxamide 3.04 (s, 2H), 2.62-2.66 (m, 4H). Example N-(azetidin-3- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.27 (t, MS 470 ylmethyl)-6-{[5- J = 6.3Hz, 1H), 8.60-8.61 (m, 1H), 8.55 (d, (ESI) (trifluoromethyl)pyridin- J =8.8 Hz, 1H), 8.32 (dd, J = 8.9, 2.4 Hz, 1H), m/z 2- 8.18-8.22 (m, 2H),7.94 (d, J = 2.8 Hz, 1H), 403.1 yl]oxy}quinline-2- 7.77 (dd, J = 9.0,2.6 Hz, 1H), 7.41 (d, J = 8.9 Hz, [M + H]⁺ carboxamide 1H), 3.97-4.04(m, 2H), 3.85-3.92 (m, 2H), 3.60 (t, J = 6.4 Hz, 2H), 3.07-3.18 (m, 1H).Example N-(2-hydroxy-2- ¹H NMR (400 MHz, CDCl₃) δ ppm MS 471methylpropyl)-6-{[6- 9.60-9.35 (m, 1H), 9.00-8.82 (m, 1H), 8.67-8.60 (m,(ESI) (trifluoromethyl)pyridin- 1H), 8.60-8.46 (m, 2H), 7.87-7.73 (m,2H), m/z 3- 7.67-7.54 (m, 1H), 7.50-7.39 (m, 1H), 406.0yl]oxy}quinoline-2- 3.69-3.57 (m, 2H), 1.37 (s, 6H). [M + H]⁺carboxamide Example 4-{4-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59(d, ESI m/z 472 (trifluoromethyl)pyridin- J = 3.1 Hz, 1H), 8.48 (d, J =8.5 Hz, 1H), 470.1 2- 8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.11 (d, J = 9.1Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.74-7.66(m, yl)carbonyl]piperazin- 2H), 7.39 (d, J = 8.7 Hz, 1H), 3.72 (t, J =4.6 Hz, 1-yl}butanenitrile 2H), 3.46 (t, J = 4.5 Hz, 2H), 2.53-2.36 (m,8H), 1.75 (p, J = 7.0 Hz, 2H). Example 3-{4-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 473 (trifluoromethyl)pyridin- 8.61-8.57 (m, 1H),8.48 (d, J = 8.5 Hz, 1H), 456.1 2- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.11(d, J = 9.1 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 7.89 (d, J = 2.6 Hz,1H), 7.75-7.66 (m, yl)carbonyl]piperazin- 2H), 7.39 (d, J = 8.7 Hz, 1H),3.72 (t, J = 4.6 Hz, 1-yl}propanenitrile 2H), 3.48 (t, J = 4.6 Hz, 2H),2.74-2.45 (m, 8H). Example 1-[(6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppmESI m/z 474 (trifluoromethyl)pyridin- 8.59 (bs, 1H), 8.49 (d, J = 8.4Hz, 1H), 8.30 (dd, J = 8.7, 427.1 2- 2.6 Hz, 1H), 8.11 (d, J = 9.0 Hz,1H), [M + H]⁺ yl]oxy}quinolin-2- 7.89 (d, J = 2.6 Hz, 1H), 7.73 (s, 1H),7.71 (s, 1H), yl)carbonyl]piperidine- 7.39 (d, J = 8.7 Hz, 1H),4.07-3.97 (m, 1H), 4-carbonitrile 3.65-3.55 (m, 1H), 3.53-3.43 (m, 1H),3.37 (m, 1H), 3.26-3.14 (m, 1H), 2.10-1.97 (m, 1H), 1.98-1.86 (m, 1H),1.88-1.72 (m, 2H). Example 6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.58(d, ESI m/z 475 (difluoromethyl)pyridin- J = 6.9 Hz, 1H), 8.53 (d, J =8.5 Hz, 1H), 372.1 2-yl]oxy}-N- 8.43-8.39 (m, 1H), 8.24 (d, J = 9.1 Hz,1H), [M + H]⁺ (oxetan-3- 8.17-8.11 (m, 2H), 7.89 (d, J = 2.6 Hz, 1H),yl)quinoline-2- 7.75 (dd, J = 9.1, 2.7 Hz, 1H), 7.34 (d, J = 8.5 Hz,carboxamide 1H), 5.11 (h, J = 7.1 Hz, 1H), 4.82-4.73 (m, 4H). Example5,8-dioxa-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (d, ESI m/z 476azaspiro[3.4]oct-2- J = 2.9 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), 432.1yl(6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.18 (d, J = 9.0 Hz, [M + H]⁺(trifluoromethyl)pyridin- 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.90 (d, J =2.6 Hz, 2- 1H), 7.73 (dd, J = 9.0, 2.7 Hz, 1H), yl]oxy}quinolin-2- 7.40(d, J = 8.6 Hz, 1H), 4.86 (bs, 2H), 4.26 (bs, yl)methanone 2H),4.00-3.96 (m, 4H). Example 6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.88(d, ESI m/z 477 (difluoromethyl)pyridin- J = 8.1 Hz, 1H), 8.57 (d, J =8.5 Hz, 1H), 450.0 2-yl]oxy}-N- 8.44-8.39 (m, 1H), 8.21 (s, 1H), 8.20(s, 1H), [M + H]⁺ [(3S,4S)-4-hydroxy- 8.15 (dd, J = 8.5, 2.3 Hz, 1H),7.91 (d, J = 2.6 Hz, 1,1- 1H), 7.75 (dd, J = 9.1, 2.6 Hz, 1H), 7.34 (d,J = 8.5 Hz, dioxidotetrahydrothiophen- 1H), 7.13 (t, J = 55.3 Hz, 1H),6.30 (s, 3-yl]quinoline- 1H), 4.85-4.75 (m, 1H), 4.66-4.61 (m, 1H),2-carboxamide 3.61-3.46 (m, 2H), 3.42-3.30 (m, 2H). Exampletetrahydro-5H- ¹H NMR (500 MHz, DMSO-d₆) δ ppm ESI m/z 478[1,3]dioxolo[4,5- 8.60 (bs, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.31 (dd, J =8.7, 432.1 c]pyrrol-5-yl(6-{[5- 2.6 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H),[M + H]⁺ (trifluoromethyl)pyridin- 7.90 (d, J = 2.6 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 2- 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.40 (d, J = 8.6 Hz,yl]oxy}quinolin-2- 1H), 5.06 (s, 1H), 4.82-4.73 (m, 2H), yl)methanone4.76-4.69 (m, 1H), 4.11-4.07 (m, 1H), 4.08-4.00 (m, 1H), 3.89 (dd, J =13.3, 5.2 Hz, 1H), 3.60 (dd, J = 13.8, 5.5 Hz, 1H). Example (6-{[5- ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.51 (d, ESI m/z 479(difluoromethyl)pyridin- J = 8.5 Hz, 1H), 8.42-8.38 (m, 1H), 8.21 (d, J= 9.1 Hz, 434.0 2-yl]oxy}quinolin- 1H), 8.14 (dd, J = 8.7, 2.4 Hz, 1H),[M + H]⁺ 2-yl)[3- 8.08 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 2.6 Hz,(methylsulfonyl)azetidin- 1H), 7.73 (dd, J = 9.0, 2.6 Hz, 1H), 7.33 (d,J = 8.5 Hz, 1-yl]methanone 1H), 7.12 (t, J = 55.3 Hz, 1H), 5.09 (dd, J =11.7, 6.9 Hz, 1H), 4.99 (dd, J = 11.5, 3.9 Hz, 1H), 4.47-4.38 (m, 2H),4.37-4.27 (m, 1H), 3.10 (s, 3H). Example N-methyl-N-(oxetan- ¹H NMR (500MHz, DMSO-d₆) δ ppm ESI m/z 480 3-yl)-6-{[5- 8.59 (bs, 1H), 8.49 (dd, J= 8.5, 5.5 Hz, 1H), 404.1 (trifluoromethyl)pyridin- 8.31 (dd, J = 8.7,2.5 Hz, 1H), 8.12 (dd, J = 19.2, [M + H]⁺ 2- 9.1 Hz, 1H), 7.90 (d, J =2.6 Hz, 1H), yl]oxy}quinoline-2- 7.77-7.65 (m, 2H), 7.40 (d, J = 8.7 Hz,1H), 5.41 carboxamide and 5.13 (2m, 1H), 4.78 and 4.63 (2t, J = 7.3 Hz,4H), 3.28 and 3.11 (2s, 3H). Example 6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δppm ESI m/z 481 (difluoromethyl)pyridin- 9.03-8.81 (m, 1H), 8.52 (d, J =8.5 Hz, 1H), 432.1 2-yl]oxy}-N-(1- 8.41 (bs, 1H), 8.22 (dd, J = 9.1, 3.5Hz, 1H), [M + H]⁺ oxidotetrahydro-2H- 8.18-8.11 (m, 2H), 7.88 (d, J =2.6 Hz, 1H), thiopyran-4- 7.73 (dd, J = 9.1, 2.7 Hz, 1H), 7.33 (d, J =8.5 Hz, yl)quinoline-2- 1H), 7.13 (t, J = 55.3 Hz, 1H), 4.34-4.04 (m,carboxamide 1H), 3.41-3.11 (m, 1H), 3.01-2.78 (m, 3H), 2.43-1.80 (m,4H). Example N-(oxetan-3- ¹H NMR (400 MHz, DMSO-d₆₎ δ ppm 9.16 (t, MS482 ylmethyl)-6-{[5- J = 6.1 Hz, 1H), 8.61-8.62 (m, 1H), 8.53 (d, (ESI)(trifluoromethyl)pyridin- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz,1H), m/z 2- 8.17-8.21 (m, 2H), 7.93 (d, J = 2.8 Hz, 1H), 404.1yl]oxy}quinoline-2- 7.76 (dd, J = 9.2, 2.8 Hz, 1H), 7.40 (d, J = 8.5 Hz,[M + H]⁺ carboxamide 1H), 4.64-4.67 (m, 2H), 4.40-4.43 (m, 2H),3.65-3.68 (m, 2H), 3.22-3.30 (m, 1H). Example 4-[(6-{[5- ¹H NMR (500MHz, DMSO-d₆, rotamers) δ MS 483 (trifluoromethyl)pyridin- ppm 8.59 (s,1H), 8.51 (dd, J = 8.5, 3.1 Hz, (ESI) 2- 1H), 8.30 (dd, J = 8.7, 2.4 Hz,1H), 8.12 (dd, J = 9.1, m/z yl]oxy}quinolin-2- 5.5 Hz, 1H), 7.92-7.88(m, 1H), 428.0 yl)carbonyl]piperazine- 7.75-7.67 (m, 2H), 7.39 (d, J =8.7 Hz, 1H), 4.51 (d, [M + H]⁺ 2-carbonitrile J = 13.2 Hz, 0.5H), 4.38(d, J = 12.8 Hz, 0.5H), 4.33-4.30 (m, 0.5H), 4.10-4.00 (m, 1H), 3.73 (d,J = 13.2 Hz, 0.5H), 3.54-3.46 (m, 1.5H), 3.30-3.18 (m, 1H), 3.08-2.99(m, 0.5H), 2.97-2.81 (m, 1.5H), 2.79-2.71 (m, 0.5H). Example6-(4-cyanophenoxy)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.87 (d, MS 484N-(2-oxopiperidin-4- J = 8.1 Hz, 1H), 8.51 (d, J = 8.6 Hz, 1H), (ESI)yl)quinoline-2- 8.25 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), m/zcarboxamide 7.92 (d, J = 8.7 Hz, 2H), 7.75-7.73 (m, 1H), 387.0 7.72-7.68(m, 1H), 7.58 (s, 1H), 7.30 (d, J = 8.7 Hz, [M + H]⁺ 2H), 4.35-4.21 (m,1H), 3.26-3.17 (m, 2H), 2.55-2.44 (m, 2H), 2.03-1.81 (m, 2H). ExampleN-(3,3- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 485difluorocyclopentyl)- 1.94-2.04 (m, 1H), 2.05-2.24 (m, 2H), 438.0 6-{[5-2.25-2.57 (m, 3H), 4.46-4.64 (m, 1H), 7.41 (d, J = 8.7 Hz, M + H]⁺(trifluoromethyl)pyridin- 1H), 7.72-7.82 (m, 1H), 7.93 (t, J = 4.2 Hz,2- 1H), 8.15 (dd, J = 14.7, 8.5 Hz, 1H), yl]oxy}quinoline-2- 8.23 (d, J= 9.1 Hz, 1H), 8.27-8.37 (m, 1H), carboxamide 8.53 (t, J = 9.0 Hz, 1H),8.61 (d, J = 7.4 Hz, 1H), 9.03-9.12 (m, 1H) Example N-(3,3- ¹H NMR (500MHz, DMSO-d₆) δ ppm DCI m/z 486 difluorocyclopentyl)- 1.99 (ddd, J =12.0, 10.3, 5.9 Hz, 1H), 420.0 6-{[5- 2.06-2.24 (m, 2H), 2.23-2.43 (m,2H), 2.45-2.58 (m, [M + H]⁺ (difluoromethyl)pyridin- 1H), 4.43-4.64 (m,1H), 7.13 (t, J = 55.3 Hz, 2- 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.73 (dd, J= 9.1, yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.89 (d, J = 2.6 Hz, 1H), 8.15(t, J = 7.5 Hz, carboxamide 2H), 8.21 (d, J = 9.1 Hz, 1H), 8.41 (s, 1H),8.53 (d, J = 8.6 Hz, 1H), 9.07 (d, J = 8.1 Hz, 1H) Example [3-fluoro-3-¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 487(methoxymethyl)pyrrolidin- 8.58-8.40 (m, 2H), 8.22 (dd, J = 8.7, 2.6 Hz,(APCI) 1-yl](6-{[5- 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.91-7.78 (m, m/z(trifluoromethyl)pyridin- 2H), 7.68 (dd, J = 9.1, 2.7 Hz, 1H), 7.33 (d,J = 8.8 Hz, 450.2 2- 1H), 4.08-3.58 (m, 6H), 3.37 (d, J = 28.6 Hz, [M +H]⁺ yl]oxy}quinolin-2- 3H), 2.27-2.06 (m, 2H). yl)methanone Example[3-(ethoxymethyl)-3- ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 488fluoropyrrolidin-1- 8.58-8.40 (m, 2H), 8.22 (dd, J = 8.7, 2.6 Hz, (APCI)yl](6-{[5- 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.91-7.78 (m, m/z(trifluoromethyl)pyridin- 2H), 7.68 (dd, J = 9.2, 2.6 Hz, 1H), 7.33 (d,J = 8.7 Hz, 464.3 2- 1H), 4.09-3.48 (m, 8H), 2.18 (ddd, J = 28.4, [M +H]⁺ yl]oxy}quinolin-2- 11.7, 7.0 Hz, 2H), 1.14 (dt, J = 26.5,yl)methanone 6.8 Hz, 3H). Example {3-fluoro-3-[(pyridin- ¹H NMR (400MHz, DMSO-d₆, 90° C.) δ ppm MS 489 4- 8.53 (s, 4H), 8.47 (d, J = 8.5 Hz,1H), 8.23 (dd, (APCI) yloxy)methyl]pyrrolidin- J = 8.8, 2.6 Hz, 1H),8.15 (s, 1H), 7.89 (s, 1H), m/z 1-yl}(6-{[5- 7.83 (d, J = 2.6 Hz, 1H),7.69 (dd, J = 9.1, 2.6 Hz, 513.2 (trifluoromethyl)pyridin- 1H), 7.40 (s,1H), 7.34 (d, J = 8.6 Hz, 2H), [M + H]⁺ 2- 4.69 (d, J = 23.7 Hz, 2H),4.04 (s, 4H), yl]oxy}quinolin-2- 2.43-2.27 (m, 3H). yl)methanone Example{3-fluoro-3-[(pyridin- ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 490 3-8.53 (s, 1H), 8.50-8.30 (m, 2H), 8.22 (dd, J = 8.7, (APCI)yloxy)methyl]pyrrolidin- 2.7 Hz, 2H), 8.14 (d, J = 13.2 Hz, 1H), m/z1-yl}(6-{[5- 7.89 (s, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.69 (dd, 513.2(trifluoromethyl)pyridin- J = 9.1, 2.7 Hz, 1H), 7.62-7.36 (m, 2H), [M +H]⁺ 2- 7.33 (d, J = 8.7 Hz, 1H), 4.57-4.38 (m, 2H), yl]oxy}quinolin-2-4.12 (d, J = 85.5 Hz, 4H), 2.35 (d, J = 14.8 Hz, 2H). yl)methanoneExample [3-fluoro-3- ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 491(phenoxymethyl)pyrrolidin- 8.58-8.41 (m, 2H), 8.22 (dd, J = 8.7, 2.6 Hz,(APCI) 1-yl](6-{[5- 1H), 8.15 (dd, J = 17.3, 9.1 Hz, 1H), 7.88 (d, J =8.6 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.83 (d, J = 2.6 Hz, 1H),512.2 2- 7.69 (dd, J = 9.1, 2.6 Hz, 1H), 7.31 (dd, J = 16.0, [M + H]⁺yl]oxy}quinolin-2- 8.5 Hz, 3H), 7.08-6.92 (m, 3H), yl)methanone4.45-3.74 (m, 6H), 2.40-2.21 (m, 2H). Example benzyl ({4-fluoro-1- ¹HNMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 492 [(6-{[5- 8.53 (s, 1H), 8.45(d, J = 8.5 Hz, 1H), 8.22 (dd, (APCI) (trifluoromethyl)pyridin- J = 8.7,2.6 Hz, 1H), 8.14 (dd, J = 9.3, 5.6 Hz, m/z 2- 1H), 7.93-7.78 (m, 2H),7.73-7.63 (m, 1H), 569.2 yl]oxy}quinolin-2- 7.40-7.23 (m, 5H), 5.27 (dd,J = 53.9, 16.2 Hz, [M + H]⁺ yl)carbonyl]pyrrolidin- 1H), 5.04 (d, J =28.8 Hz, 2H), 3- 4.31-3.30 (m, 5H), 3.20 (dd, J = 13.7, 7.8 Hz, 1H),yl}methyl)carbamate 2.72-2.54 (m, 1H). Example {3-fluoro-3-[(2- ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ ppm MS 493 methoxyethoxy)methyl]pyrrolidin-8.58-8.36 (m, 2H), 8.22 (dd, J = 8.6, 2.6 Hz, (APCI) 1-yl}(6- 1H), 8.15(s, 1H), 7.91-7.78 (m, 2H), m/z {[5- 7.68 (dd, J = 9.1, 2.7 Hz, 1H),7.33 (d, J = 8.7 Hz, 494.2 (trifluoromethyl)pyridin- 1H), 4.12-3.41 (m,9H), 3.30 (s, 1H), 3.23 (s, [M + H]⁺ 2- 3H), 2.27-2.09 (m, 2H).yl]oxy}quinolin-2- yl)methanone Example 2-oxa-6- ¹H NMR (400 MHz,DMSO-d₆, 90° C.) δ ppm MS 494 azaspiro[3.4]oct-6- 8.57-8.48 (m, 1H),8.44 (d, J = 8.5 Hz, 1H), (APCI) yl(6-{[5- 8.22 (dd, J = 8.8, 2.5 Hz,1H), 8.14 (d, J = 13.4 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.87-7.77(m, 2H), 7.68 (dd, J = 9.3, 430.2 2- 3.6 Hz, 1H), 7.33 (d, J = 8.7 Hz,1H), [M + H]⁺ yl]oxy}quinolin-2- 4.95-4.32 (m, 4H), 4.04-3.39 (m, 4H),2.23 (t, J = 7.1 Hz, yl)methanone 2H). Example [(2R,4S)-4-fluoro-2- ¹HNMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 495 (hydroxymethyl)pyrrolidin-8.61-8.50 (m, 1H), 8.46 (d, J = 8.5 Hz, 1H), (APCI) 1-yl](6-{[5- 8.22(dd, J = 8.7, 2.5 Hz, 1H), 8.14 (d, J = 9.1 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.82 (d, J = 2.7 Hz, 2H), 7.69 (dd, J =9.1, 436.2 2- 2.6 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 5.31 (d, J = 54.0 Hz, 1H), 5.01-3.50 (m, 4H),yl)methanone 2.31 (d, J = 29.3 Hz, 2H). Example [(2R)-4,4-difluoro-2- ¹HNMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 496 (hydroxymethyl)pyrrolidin-8.53 (d, J = 2.5 Hz, 1H), 8.47 (d, J = 8.5 Hz, (APCI) 1-yl](6-{[5- 1H),8.22 (dd, J = 8.7, 2.7 Hz, 1H), 8.17 (d, J = 9.2 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.83 (d, 454.22- J = 2.6 Hz, 1H), 7.69 (dd, J = 9.1, 2.6 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.34 (d, J = 8.8 Hz, 1H), 5.05-3.35 (m, 5H),yl)methanone 2.76-2.52 (m, 2H). Example [(2S)-4,4-difluoro-2- ¹H NMR(400 MHz, DMSO-d₆, 90° C.) δ ppm MS 497 (hydroxymethyl)pyrrolidin-8.62-8.51 (m, 1H), 8.47 (d, J = 8.6 Hz, 1H), (APCI) 1-yl](6-{[5- 8.23(dd, J = 8.8, 2.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.90 (dd, J = 17.9, 8.5 Hz, 1H), 454.2 2-7.83 (d, J = 2.6 Hz, 1H), 7.69 (dd, J = 9.1, 2.6 Hz, [M + H]⁺yl]oxy}quinolin-2- 1H), 7.34 (d, J = 8.8 Hz, 1H), 5.09-3.34 (m,yl)methanone 5H), 2.95-2.54 (m, 2H). Example 1-(3- 1H NMR (500 MHz,DMSO-d₆) δ ppm MS 498 methoxyphenyl)-4- 3.76 (d, J = 3.36 Hz, 3 H)3.78-3.91 (m, 2 H) (ESI) [(6-{[5- 3.96-4.12 (m, 2 H) 4.47 (d, J = 19.84Hz, 2 H) m/z (trifluoromethyl)pyridin- 6.82-6.91 (m, 1 H) 6.91-7.03 (m,2 H) 523.0 2- 7.28-7.35 (m, 1 H) 7.40 (dd, J = 8.54, 2.75 Hz, 1 H) [M +H]⁺ yl]oxy}quinolin-2- 7.67-7.78 (m, 1 H) 7.85 (dd, J = 12.82, 8.54 Hz,1 H) yl)carbonyl]piperazin- 7.90-7.96 (m, 1 H) 8.16 (d, J = 9.16 Hz, 1H) 2-one 8.31 (dd, J = 8.85, 2.44 Hz, 1 H) 8.53 (d, J = 8.54 Hz, 1 H)8.59 (s, 1 H) Example N-(thietan-3-yl)-6- ¹H NMR (500 MHz, DMSO-d₆) δppm 9.58 (d, ESI m/z 499 {[5- J = 8.4 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H),406.0 (trifluoromethyl)pyridin- 8.53 (d, J = 8.5 Hz, 1H), 8.32 (dd, J =8.7, 2.6 Hz, [M + H]⁺ 2- 1H), 8.23 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 8.4Hz, yl]oxy}quinoline-2- 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.77 (dd, J =9.1, carboxamide 2.6 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 5.38-5.26 (m,1H), 3.76 (t, J = 8.9 Hz, 2H), 3.28-3.21 (m, 2H). Example N-{3-[(2- 1HNMR (500 MHz, DMSO-d₆) δ ppm MS 500 methylphenyl)amino]- 2.17 (s, 3 H)2.73 (t, J = 6.71 Hz, 2 H) 3.70 (q, (ESI) 3-oxopropyl}-6-{[5- J = 6.61Hz, 2 H) 7.07 (t, J = 7.32 Hz, 1 H) m/z (trifluoromethyl)pyridin-7.11-7.22 (m, 2 H) 7.40 (t, J = 8.24 Hz, 2 H) 495.0 2- 7.76 (dd, J =9.16, 2.44 Hz, 1 H) 7.93 (d, J = 2.75 Hz, [M + H]⁺ yl]oxy}quinoline-2- 1H) 8.13-8.23 (m, 2 H) 8.31 (dd, J = 8.54, carboxamide 2.44 Hz, 1 H) 8.55(d, J = 8.54 Hz, 1 H) 8.61 (s, 1 H) 8.99 (t, J = 5.80 Hz, 1 H) 9.40 (s,1 H) Example N-[(2S)-1- 1H NMR (500 MHz, DMSO-d₆) δ ppm MS 501(dimethylamino)-1- 2.84 (s, 3 H) 2.94 (s, 3 H) 3.05-3.16 (m, 2 H) (ESI)oxo-3-phenylpropan- 5.20-5.28 (m, 1 H) 7.18-7.30 (m, 5 H) 7.41 (d, m/z2-yl]-6-{[5- J = 8.55 Hz, 1 H) 7.77 (dd, J = 9.16, 2.44 Hz, 1 509.0(trifluoromethyl)pyridin- H) 7.93 (d, J = 2.44 Hz, 1 H) 8.13 (d, J =8.54 Hz, [M + H]⁺ 2- 1 H) 8.22 (d, J = 9.16 Hz, 1 H) 8.32 (dd,yl]oxy}quinoline-2- J = 8.85, 2.44 Hz, 1 H) 8.54 (d, J = 8.85 Hz, 1 H)carboxamide 8.61 (s, 1 H) 8.86 (d, J = 8.24 Hz, 1 H) Example N-[1-(2- 1HNMR (400 MHz, DMSO-d₆) δ ppm MS 502 methoxyphenyl)-5- 2.70-2.91 (m, 2 H)3.77 (dd, J = 9.61, 5.04 Hz, 1 H) (ESI) oxopyrrolidin-3-yl]- 3.83 (s, 3H) 4.02 (dd, J = 9.77, 7.32 Hz, 1 H) m/z 6-{[5- 4.77-4.89 (m, 1 H) 6.99(t, J = 7.48 Hz, 1 H) 523.0 (trifluoromethyl)pyridin- 7.13 (d, J = 8.24Hz, 1 H) 7.32 (t, J = 7.02 Hz, 2 [M + H]⁺ 2- H) 7.41 (d, J = 8.85 Hz, 1H) 7.78 (dd, J = 9.16, yl]oxy}quinoline-2- 2.44 Hz, 1 H) 7.94 (d, J =2.44 Hz, 1 H) 8.19 (d, carboxamide J = 8.55 Hz, 1 H) 8.25 (d, J = 9.16Hz, 1 H) 8.32 (dd, J = 8.70, 2.59 Hz, 1 H) 8.55 (d, J = 8.85 Hz, 1 H)8.62 (s, 1 H) 9.29 (d, J = 7.32 Hz, 1 H) Example N-(1-oxidothietan-3- ¹HNMR (500 MHz, DMSO-d₆) δ ppm ESI m/z 503 yl)-6-{[5- 9.56 (m, 1H), 8.62(bs, 1H), 8.55 (d, J = 8.5 Hz, 422.0 (trifluoromethyl)pyridin- 1H), 8.32(dd, J = 8.7, 2.6 Hz, 1H), 8.23 (d, J = 9.1 Hz, [M + H]⁺ 2- 1H), 8.17(d, J = 8.3 Hz, 1H), 7.94 (d, yl]oxy}quinoline-2- J = 2.6 Hz, 1H),7.81-7.75 (m, 1H), 7.41 (d, J = 8.7 Hz, carboxamide 1H), 5.43 and 4.50(2m, 1H), 4.08-3.79 (m, 2H), 3.63-3.36 (m, 2H). Example N-(1,1- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.61 (d, ESI m/z 504 dioxidothietan-3-yl)- J =6.1 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 438.1 6-{[5- 8.56 (d, J = 8.5 Hz,1H), 8.32 (dd, J = 8.7, 2.6 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H),8.23 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2- 1H), 7.95 (d, J = 2.6Hz, 1H), 7.79 (dd, J = 9.1, yl]oxy}quinoline-2- 2.7 Hz, 1H), 7.41 (d, J= 8.6 Hz, 1H), carboxamide 4.78-4.65 (m, 1H), 4.63-4.49 (m, 4H). Example6-oxa-1- ¹H NMR (400 MHz, DMSO-d₆) δ 6 ppm ESI m/z 505azaspiro[3.3]hept-1- 8.60 (m, 1H), 8.49 (m, 1H), 8.28 (m, 1H), 8.11 (m,416.0 yl(6-{[5- 2H), 7.91 (m, 1H), 7.72 (m, 1H), 7.39 (m, 1H), [M + H]⁺(trifluoromethyl)pyridin- 5.36 (m, 2H), 4.61 (m, 4H), 2.66 (m, 2H). 2-yl]oxy}quinolin-2- yl)methanone Example 1-{1-[(6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 506 (trifluoromethyl)pyridin- 8.62-8.58 (m, 1H),8.49 (d, J = 8.5 Hz, 1H), 416.1 2- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.17(d, J = 9.1 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 8.05 (d, J = 8.5 Hz,1H), 7.90 (d, J = 2.6 Hz, yl)carbonyl]azetidin- 1H), 7.73 (dd, J = 9.1,2.7 Hz, 1H), 3-yl}ethanone 7.40 (d, J = 8.7 Hz, 1H), 4.90 (t, J = 9.7Hz, 1H), 4.79 (dd, J = 10.3, 6.0 Hz, 1H), 4.29-4.16 (m, 2H), 3.81-3.69(m, 1H), 2.20 (s, 3H). Example (3-fluoroazetidin-1- ¹H NMR (500 MHz,DMSO-d₆) δ ppm ESI m/z 507 yl)(6-{[5- 8.60 (bs, 1H), 8.50 (d, J = 8.5Hz, 1H), 8.31 (dd, J = 8.7, 392.1 (trifluoromethyl)pyridin- 2.6 Hz, 1H),8.18 (d, J = 9.0 Hz, 1H), [M + H]⁺ 2- 8.08 (d, J = 8.5 Hz, 1H), 7.91 (d,J = 2.6 Hz, 1H), yl]oxy}quinolin-2- 7.74 (dd, J = 9.0, 2.6 Hz, 1H), 7.40(d, J = 8.6 Hz, yl)methanone 1H), 5.56 and 5.46 (2m, 1H), 5.08 (dddd, J= 22.4, 12.2, 5.8, 2.0 Hz, 1H), 4.89-4.78 (m, 1H), 4.49 (dddd, J = 21.6,12.0, 6.0, 1.9 Hz, 1H), 4.25-4.13 (m, 1H). Example(3,3-difluoroazetidin- ¹H NMR (500 MHz, DMSO-d₆) δ ppm ESI m/z 5081-yl)(6-{[5- 8.60 (bs, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7,410.0 (trifluoromethyl)pyridin- 2.6 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H),[M + H]⁺ 2- 8.11 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H),yl]oxy}quinolin-2- 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz,yl)methanone 1H), 5.26-5.17 (m, 2H), 4.63-4.54 (m, 2H). Example(4R)-4-fluoro-N,N- ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm MS 509dimethyl-1-[(6-{[5- 8.57-8.34 (m, 2H), 8.25-8.02 (m, 2H), (APCI)(trifluoromethyl)pyridin- 7.97-7.74 (m, 2H), 7.74-7.59 (m, 1H), 7.30 (d,J = 8.7 Hz, m/z 2- 1H), 5.89-5.12 (m, 1H), 4.07 (d, J = 72.2 Hz, 477.1yl]oxy}quinolin-2- 1H), 3.07 (s, 6H), 2.90-2.58 (m, [M + H]⁺yl)carbonyl]-L- 3H), 2.44-2.03 (m, 1H). prolinamide Example[4-(1,3-oxazol-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.37 (s, DCI m/z 510ylmethyl)piperazin-1- 3H), 2.40-2.46 (m, 2H), 2.52-2.59 (m, 2H), 484.0yl](6-{[5- 3.35-3.56 (m, 4H), 3.61-3.79 (m, 2H), M + H]⁺(trifluoromethyl)pyridin- 7.39 (d, J = 8.7 Hz, 1H), 7.65-7.75 (m, 2H),2- 7.76-7.94 (m, 2H), 8.11 (t, J = 7.7 Hz, 1H), yl]oxy}quinolin-2- 8.30(dd, J = 8.7, 2.4 Hz, 1H), 8.48 (t, J = 7.3 Hz, yl)methanone 1H), 8.58(s, 1H) Example N-(4,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (d, MS 511difluorocyclohexyl)- J = 8.6 Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.51 (d,(ESI) 6-{[6- J = 8.6 Hz, 1H), 8.25 (d, J = 10.1 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.15 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz,1H), 452.1 3- 7.76-7.82 (m, 3H), 4.03-4.10 (m, 1H), [M + H]⁺yl]oxy}quinoline-2- 1.76-2.09 (m, 8H). carboxamide Example N-[(4S)-2- ¹HNMR (500 MHz, DMSO-d₆) δ 8.89 (d, J = 8.1 Hz, (ESI) 512oxopiperidin-4-yl]-6- 1H), 8.63-8.60 (m, 1H), 8.54 (d, J = 8.6 Hz, m/z{[5- 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 431.0(trifluoromethyl)pyridin- 8.23 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 8.5 Hz,[M + H]⁺ 2- 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1,yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.60 (s, 1H), 7.40 (d, J = 8.8 Hz,carboxamide 1H), 4.34-4.24 (m, 1H), 3.26-3.20 (m, 2H), 2.55-2.42 (m,2H), 2.04-1.96 (m, 1H), 1.95-1.83 (m, 1H). Example N-[2-oxo-2- ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ ppm MS 513 (pyrrolidin-1- 8.62 (d, J = 2.7 Hz,1H), 8.50 (d, J = 8.5 Hz, 1H), (ESI) yl)ethyl]-6-{[6- 8.24 (d, J = 10.1Hz, 1H), 8.17 (d, J = 8.5 Hz, m/z (trifluoromethyl)pyridin- 1H),7.71-7.77 (m, 3H), 4.18 (s, 2H), 445.2 3- 3.37-3.53 (m, 4H), 1.80-1.99(m, 4H). [M + H]⁺ yl]oxy}quinoline-2- carboxamide Example N-{2-[(2- ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 514 methoxyethyl)amino]- 8.60 (d, J= 2.7 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), (ESI) 2-oxoethyl}-N- 8.13 (d, J= 8.2 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), m/z methyl-6-{[6- 7.67-7.74 (m,4H), 4.17 (s, 2H), 3.19-3.32 (m, 463.2 (trifluoromethyl)pyridin- 7H),3.08 (s, 3H). [M + H]⁺ 3- yl]oxy}quinoline-2- carboxamide ExampleN-[3-(morpholin-4- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 515yl)-3-oxopropyl]-6- 8.61 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H),(ESI) {[6- 8.22 (d, J = 9.8 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.92 (d, J = 8.5 Hz, 1H), 7.70-7.76 (m, 3H),475.3 3- 3.65 (t, J = 6.7 Hz, 2H), 3.57-3.59 (m, 4H), [M + H]⁺yl]oxy}quinoline-2- 3.47-3.50 (m, 4H), 2.69 (t, J = 6.7 Hz, 2H).carboxamide Example N-[3-oxo-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS516 (pyrrolidin-1- 8.61 (d, J = 3.1 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H),(ESI) yl)propyl]-6-{[6- 8.22 (d, J = 9.8 Hz, 1H), 8.15 (d, J = 8.5 Hz,1H), m/z (trifluoromethyl)pyridin- 7.92 (d, J = 8.5 Hz, 1H), 7.70-7.76(m, 3H), 459.3 3- 3.64 (t, J = 6.7 Hz, 2H), 333-3.45 (m, 4H), [M + H]⁺yl]oxy}quinoline-2- 2.69 (t, J = 6.7 Hz, 2H), 1.77-1.91 (m, 4H).carboxamide Example N-[2-(diethylamino)- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δppm MS 517 2-oxoethyl]-6-{[6- 8.62 (d, J = 3.1 Hz, 1H), 8.50 (d, J = 8.5Hz, 1H), (ESI) (trifluoromethyl)pyridin- 8.24 (d, J = 10.1 Hz, 1H), 8.17(d, J = 8.5 Hz, m/z 3- 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.71-7.77 (m,447.2 yl]oxy}quinoline-2- 3H), 4.26 (s, 2H), 3.38 (q, J = 7.0 Hz, 4H),[M + H]⁺ carboxamide 1.16 (t, J = 7.0 Hz, 6H). Example N-[2-oxo-2- ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 518 (piperidin-1- 8.62 (d, J = 2.7Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), (ESI) yl)ethyl]-6-{[6- 8.24 (d, J =10.1 Hz, 1H), 8.17 (d, J = 8.5 Hz, m/z (trifluoromethyl)pyridin- 1H),7.92 (d, J = 8.5 Hz, 1H), 7.71-7.77 (m, 459.3 3- 3H), 4.25 (s, 2H),3.46-3.49 (m, 4H), [M + H]⁺ yl]oxy}quinoline-2- 1.50-1.66 (m, 6H).carboxamide Example N-(1-methyl-5- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppmMS 519 oxopyrrolidin-3-yl)- 8.61 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 8.5Hz, 1H), (ESI) 6-{[6- 8.26 (d, J = 9.8 Hz, 1H), 8.13 (d, J = 8.5 Hz,1H), m/z (trifluoromethyl)pyridin- 7.92 (d, J = 8.5 Hz, 1H), 7.70-7.77(m, 3H), 431.2 3- 4.62-4.69 (m, 1H), 3.77 (dd, J = 10.1, 7.6 Hz, [M +H]⁺ yl]oxy}quinoline-2- 1H), 3.44 (dd, J = 10.2, 4.7 Hz, 1H), 2.79 (s,carboxamide 3H), 2.71 (dd, J = 17.1, 8.9 Hz, 1H), 2.47-2.54 (m, 1H).Example N-[3-oxo-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 520(piperidin-1- 8.61 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 8.9 Hz, 1H), (ESI)yl)propyl]-6-{[6- 8.21 (d, J = 10.1 Hz, 1H), 8.15 (d, J = 8.5 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.69-7.76 (m,473.3 3- 3H), 3.63 (t, J = 6.7 Hz, 2H), 3.43-3.46 (m, 4H), [M + H]⁺yl]oxy}quinoline-2- 2.67 (t, J = 6.7 Hz, 2H), 1.56-1.61 (m, 2H),carboxamide 1.44-1.53 (m, 4H). Example N-[(4R)-2- ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.89 (d, (ESI) 521 oxopiperidin-4-yl]-6- J = 8.1 Hz, 1H),8.63-8.60 (m, 1H), 8.54 (d, J = 8.6 Hz, m/z {[5- 1H), 8.31 (dd, J = 8.7,2.5 Hz, 1H), 431.0 (trifluoromethyl)pyridin- 8.23 (d, J = 9.1 Hz, 1H),8.17 (d, J = 8.5 Hz, [M + H]⁺ 2- 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.76(dd, J = 9.1, yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.60 (s, 1H), 7.40 (d, J= 8.8 Hz, carboxamide 1H), 4.34-4.24 (m, 1H), 3.26-3.20 (m, 2H),2.55-2.42 (m, 2H), 2.04-1.96 (m, 1H), 1.95-1.83 (m, 1H). Example N-[2-¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 522 (cyclopropylamino)- 8.60 (d,J = 2.4 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), (ESI) 2-oxoethyl]-N- 8.12 (d,J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), m/z methyl-6-{[6- 7.67-7.74(m, 4H), 4.12 (s, 2H), 3.07 (s, 3H), 445.2 (trifluoromethyl)pyridin-2.59-2.69 (m, 1H), 0.31-0.67 (m, 4H). [M + H]⁺ 3- yl]oxy}quinoline-2-carboxamide Example N-(1-ethyl-5- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS523 oxopyrrolidin-3-yl)- 8.61 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 8.5 Hz,1H), (ESI) 6-{[6- 8.25 (d, J = 10.1 Hz, 1H), 8.13 (d, J = 8.2 Hz, m/z(trifluoromethyl)pyridin- 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.70-7.77 (m,445.2 3- 3H), 4.63-4.69 (m, 1H), 3.78 (dd, J = 10.1, 7.6 Hz, [M + H]⁺yl]oxy}quinoline-2- 1H), 3.44 (dd, J = 10.1, 4.9 Hz, 1H), carboxamide3.29 (q, J = 7.2 Hz, 2H), 2.73 (dd, J = 8.9, 16.8 Hz, 1H), 2.56 (dd, J =6.1, 16.8 Hz, 1H), 1.09 (t, J = 7.2 Hz, 2H). ExampleN-[3-(diethylamino)- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 5243-oxopropyl]-6-{[6- 8.61 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H),(ESI) (trifluoromethyl)pyridin- 8.21 (d, J = 10.1 Hz, 1H), 8.15 (d, J =8.5 Hz, m/z 3- 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.69-7.76 (m, 461.3yl]oxy}quinoline-2- 3H), 3.64 (t, J = 6.9 Hz, 2H), 3.33 (q, J = 7.0 Hz,[M + H]⁺ carboxamide 4H), 3.29 (q, J = 7.2 Hz, 2H), 2.67 (t, J = 6.7 Hz,2H), 1.09 (br s, 6H). Example N-[2- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppmMS 525 (isopropylamino)-2- 8.60 (d, J = 2.7 Hz, 1H), 8.41 (d, J = 8.5Hz, 1H), (ESI) oxoethyl]-N-methyl- 8.12 (d, J = 8.5 Hz, 1H), 7.91 (d, J= 8.5 Hz, 1H), m/z 6-{[6- 7.66-7.74 (m, 4H), 4.12 (s, 2H), 3.76-3.94 (m,447.2 (trifluoromethyl)pyridin- 1H), 3.07 (s, 3H), 1.00-1.10 (m, 6H).[M + H]⁺ 3- yl]oxy}quinoline-2- carboxamide Example [4-(morpholin-4- ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.70 (d, MS 526 yl)piperidin-1-yl](6- J =2.8 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.14 (d, (ESI) {[6- J = 9.2 Hz,1H), 7.96 (d, J = 8.9 Hz, 1H), m/z (trifluoromethyl)pyridin- 7.72-7.78(m, 3H), 7.67 (d, J = 8.5 Hz, 1H), 487.1 3- 4.51-4.57 (m, 1H), 3.71-3.74(m, 1H), 3.56-3.58 (m, [M + H]⁺ yl]oxy}quinolin-2- 4H), 3.06-3.11 (m,1H), 2.87-2.93 (m, 1H), yl)methanone 2.44-2.48 (m, 5H), 1.91-1.93 (m,1H), 1.85 (s, 3H), 1.72-1.76 (m, 1H), 1.40-1.48 (m, 2H). ExampleN-methyl-6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 527(trifluoromethyl)pyridin- 8.95-8.84 (m, 1H), 8.61 (s, 1H), 8.53 (d, J =8.6 Hz, (ESI) 2- 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.17 (dd, J = 8.8,m/z yl]oxy}quinoline-2- 3.5 Hz, 2H), 7.92 (d, J = 2.6 Hz, 1H), 348.1carboxamide 7.75 (dd, J = 9.1, 2.6 Hz, 1H), 7.40 (d, J = 8.7 Hz, [M +H]⁺ 1H), 2.91 (d, J = 4.8 Hz, 3H). Example meso-[(1R,5S,6s)-6- ¹H NMR(500 MHz, CDCl₃) δ ppm MS 528 amino-3- 8.60-8.53 (m, 1H), 8.19-8.10 (m,2H), 7.93-7.87 (m, (ESI) azabicyclo[3.1.0]hex- 1H), 7.75-7.67 (m, 1H),7.57-7.51 (m, 1H), m/z 3-yl](6-{[6- 7.50-7.44 (m, 1H), 7.43-7.36 (m,1H), 415.0 (trifluoromethyl)pyridin- 4.30-4.16 (m, 1H), 4.14-4.00 (m,3H), [M + H]⁺ 3- 3.75-3.65 (m, 1H), 0.97-0.82 (m, 2H).yl]oxy}quinolin-2- yl)methanone Example N-methyl-N-(1- ¹H NMR (500 MHz,DMSO-d₆, rotamers) δ MS 529 methyl-2- ppm 8.60-8.56 (m, 1H), 8.47 (dd, J= 8.5, 4.3 Hz, (ESI) oxopiperidin-4-yl)-6- 1H), 8.30 (dd, J = 8.7, 2.4Hz, 1H), m/z {[5- 8.13 (d, J = 9.1 Hz, 0.4H), 8.06 (d, J = 9.1 Hz, 459.0(trifluoromethyl)pyridin- 0.6H), 7.90-7.87 (m, 1H), 7.73-7.67 (m, [M +H]⁺ 2- 2H), 7.39 (d, J = 8.7 Hz, 1H), 4.84-4.74 (m, yl]oxy}quinoline-2-0.4H), 4.07-3.98 (m, 0.6H), 3.48-3.38 (m, carboxamide 0.4H), 3.38-3.34(m, 0.6H), 3.23-3.17 (m, 0.4H), 3.08 (td, J = 12.0, 4.5 Hz, 0.6H), 2.98(s, 2H), 2.88 (s, 1H), 2.85 (s, 1H), 2.69 (s, 2H), 2.66-2.52 (m, 1.6H),2.45-2.35 (m, 0.4H), 2.18-1.95 (m, 2H). Example N-[(3R)-2- 1H NMR (500MHz, DMSO-d₆) δ ppm MS 530 oxotetrahydrofuran- 2.42-2.57 (m, 2 H)4.27-4.38 (m, 1 H) (ESI) 3-yl]-6-{[5- 4.41-4.50 (m, 1 H) 4.86-4.99 (m, 1H) 7.42 (d, J = 8.85 Hz, m/z (trifluoromethyl)pyridin- 1 H) 7.78 (dd, J= 9.16, 2.75 Hz, 1 H) 418.0 2- 7.95 (d, J = 2.75 Hz, 1 H) 8.20 (dd, J =11.60, 8.85 Hz, [M + H]⁺ yl]oxy}quinoline-2- 2 H) 8.32 (dd, J = 8.54,2.44 Hz, 1 H) carboxamide 8.57 (d, J = 8.54 Hz, 1 H) 8.62 (s, 1 H) 9.49(d, J = 8.54 Hz, 1 H) Example {4-[(2-methyl-1,3- ¹H NMR (400 MHz,DMSO-d₆) δ ppm DCI m/z 531 oxazol-4- 2.31-2.46 (m, 4H), 2.52-2.59 (m,2H), 498.0 yl)methyl]piperazin- 3.35-3.56 (m, 3H), 3.61-3.79 (m, 2H),7.39 (d, J = 8.7 Hz, [M + H]⁺ 1-yl}(6-{[5- 1H), 7.65-7.75 (m, 2H),7.76-7.94 (m, (trifluoromethyl)pyridin- 2H), 8.11 (t, J = 7.7 Hz, 1H),8.30 (dd, J = 8.7, 2- 2.4 Hz, 1H), 8.48 (t, J = 7.3 Hz, 1H), 8.58 (s,yl]oxy}quinolin-2- 1H) yl)methanone Example 6-oxa-2- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 532 azaspiro[3.4]oct-2- 8.62-8.57 (m, 1H), 8.49(d, J = 8.5 Hz, 1H), 430.2 yl(6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz, 1H),8.16 (d, J = 9.1 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.07 (d, J= 8.5 Hz, 1H), 7.89 (d, J = 2.6 Hz, 2- 1H), 7.73 (dd, J = 9.0, 2.7 Hz,1H), yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 4.75 (bs, 2H), 4.12(bs, yl)methanone 2H), 3.85 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.19 (t,J = 6.9 Hz, 2H). Example 6-oxa-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm ESIm/z 533 azaspiro[3.5]non-2- 8.62-8.58 (m, 1H), 8.48 (d, J = 8.6 Hz, 1H),444.1 yl(6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.17 (d, J = 9.1 Hz,[M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.89(d, J = 2.6 Hz, 2- 1H), 7.72 (dd, J = 9.1, 2.7 Hz, 1H),yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 4.48 (m, 2H), yl)methanone3.87-3.75 (m, 2H), 3.65 (bs, 2H), 3.53 (t, J = 5.0 Hz, 2H), 1.85 (t, J =5.7 Hz, 2H), 1.59-1.50 (m, 2H). Example [3- ¹H NMR (400 MHz, DMSO-d₆) δppm 8.71 (d, ESI m/z 534 (methylsulfonyl)azetidin- J = 2.8 Hz, 1H), 8.50(d, J = 8.5 Hz, 1H), 452.1 1-yl](6-{[6- 8.25 (d, J = 9.9 Hz, 1H), 8.08(d, J = 8.5 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 7.98 (d, J = 8.6Hz, 1H), 7.83-7.75 (m, 3H), 3- 5.13-5.02 (m, 1H), 4.98 (dd, J = 11.5,3.9 Hz, yl]oxy}quinolin-2- 1H), 4.48-4.37 (m, 2H), 4.37-4.26 (m, 1H),yl)methanone 3.10 (s, 3H). Example N-(1,1- ¹H NMR (500 MHz, DMSO-d₆) δppm 9.01 (d, ESI m/z 535 dioxidotetrahydro- J = 8.4 Hz, 1H), 8.71 (d, J= 2.7 Hz, 1H), 466.1 2H-thiopyran-4-yl)-6- 8.51 (d, J = 8.5 Hz, 1H),8.25 (d, J = 9.9 Hz, 1H), [M + H]⁺ {[6- 8.14 (d, J = 8.5 Hz, 1H), 7.99(d, J = 8.6 Hz, (trifluoromethyl)pyridin- 1H), 7.84-7.74 (m, 3H),4.34-4.23 (m, 1H), 3- 3.43-3.36 (m, 2H), 3.16-3.08 (m, 2H),yl]oxy}quinoline-2- 2.34-2.20 (m, 2H), 2.18-2.10 (m, 2H). carboxamideExample N-(oxetan-3-yl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.57 (d, ESIm/z 536 {[6- J = 6.9 Hz, 1H), 8.72 (d, J = 2.8 Hz, 1H), 390.1(trifluoromethyl)pyridin- 8.51 (d, J = 8.5 Hz, 1H), 8.30-8.24 (m, 1H),[M + H]⁺ 3- 8.13 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H),yl]oxy}quinoline-2- 7.85-7.76 (m, 3H), 5.17-5.04 (m, 1H), carboxamide4.82-4.72 (m, 4H). Example N-[(3R,4S)-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.87 (d, ESI m/z 537 hydroxy-1,1- J = 8.1 Hz, 1H), 8.72 (d, J = 2.8 Hz,1H), 468.1 dioxidotetrahydrothiophen- 8.55 (d, J = 8.5 Hz, 1H),8.27-8.16 (m, 2H), [M + H]⁺ 3-yl]-6-{[6- 7.99 (d, J = 8.6 Hz, 1H),7.86-7.74 (m, 3H), (trifluoromethyl)pyridin- 6.29 (s, 1H), 4.79 (dtd, J= 11.5, 7.7, 3.7 Hz, 1H), 3- 4.62 (bs, 1H), 3.63-3.33 (m, 4H).yl]oxy}quinoline-2- carboxamide Example N-[(3S,4S)-4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.87 (d, ESI m/z 538 hydroxy-1,1- J = 8.1 Hz, 1H), 8.72(d, J = 2.8 Hz, 1H), 468.0 dioxidotetrahydrothiophen- 8.55 (d, J = 8.5Hz, 1H), 8.27-8.11 (m, 2H), [M + H]⁺ 3-yl]-6-{[6- 7.99 (d, J = 8.6 Hz,1H), 7.86-7.76 (m, 3H), (trifluoromethyl)pyridin- 6.28 (s, 1H),4.85-4.74 (m, 1H), 4.62 (bs, 1H), 3- 3.61-3.31 (m, 4H).yl]oxy}quinolin-2- carboxamide Example 2,5-dihydro-1H- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 539 pyrrol-1-yl(6-{[6- 8.70 (m, 1H), 8.47 (d, J =8.5 Hz, 1H), 8.20 (d, J = 8.9 Hz, 386.1 (trifluoromethyl)pyridin- 1H),7.97 (d, J = 8.6 Hz, 1H), 7.92 (d, [M + H]⁺ 3- J = 8.5 Hz, 1H),7.83-7.72 (m, 3H), yl]oxy}quinolin-2- 6.02-5.96 (m, 1H), 5.98-5.91 (m,1H), yl)methanone 4.69-4.63 (m, 2H), 4.42-4.36 (m, 2H). Example [4-(3,3-¹H NMR (400 MHz, DMSO-d₆₎ δ ppm MS 540 difluoroazetidin-1- 8.58-8.59 (m,1H), 8.47 (d, J = 8.6 Hz, 1H), 8.30 (dd, (ESI) yl)piperidin-1-yl](6- J =8.7, 2.6 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), m/z {[5- 7.88 (d, J = 2.8Hz, 1H), 7.67-7.72 (m, 2H), 493.1 (trifluoromethyl)pyridin- 7.39 (d, J =8.5 Hz, 1H), 4.15-4.20 (m, 1H), [M + H]⁺ 2- 3.55-3.65 (m, 5H), 3.13-3.26(m, 2H), yl]oxy}quinolin-2- 2.48-2.50 (m, 1H), 1.78-1.82 (m, 1H),1.65-1.67 (m, yl)methanone 1H), 1.23-1.35 (m, 2H). ExampleN-(2-methoxy-2- ¹H NMR (400 MHz, DMSO-d₆₎ δ ppm MS 541methylpropyl)-6-{[5- 8.61-8.62 (m, 1H), 8.56 (d, J = 8.6 Hz, 1H), 8.52(t, (ESI) (trifluoromethyl)pyridin- J = 6.3 Hz, 1H), 8.31 (dd, J = 8.7,2.6 Hz, 1H), m/z 2- 8.19-8.23 (m, 2H), 7.94 (d, J = 2.4 Hz, 1H), 420.1yl]oxy}quinoline-2- 7.76 (dd, J = 9.2, 2.4 Hz, 1H), 7.41 (d, J = 8.5 Hz,[M + H]⁺ carboxamide 1H), 3.46 (d, J = 6.4 Hz, 1H), 3.21 (s, 3H), 1.17(s, 6H). Example [(8aS)-7,7- 1H NMR (400 MHz, DMSO-d₆) δ ppm MS 542difluorohexahydropyrrolo[1, 1.73-2.14 (m, 1 H) 2.18-2.46 (m, 2 H) (ESI)2-a]pyrazin- 2.53-2.80 (m, 2 H) 2.84-3.13 (m, 2 H) 3.15-3.30 (m, 1 m/z2(1H)-yl](6-{[5- H) 3.37-3.50 (m, 1 H) 3.85 (dd, J = 51.57, 461.0(difluoromethyl)pyridin- 12.82 Hz, 1 H) 4.64 (dd, J = 48.83, 12.82 Hz, 1[M + H]⁺ 2-yl]oxy}quinolin- H) 7.12 (t, J = 55.24 Hz, 1 H) 7.32 (d, J =8.54 Hz, 2-yl)methanone 1 H) 7.64-7.73 (m, 2 H) 7.85 (d, J = 2.44 Hz, 1H) 8.06-8.16 (m, 2 H) 8.38 (s, 1 H) 8.48 (d, J = 8.54 Hz, 1 H) Example[(3R)-3- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCI m/z 543ethylpiperazin-1- ppm 0.74 (t, J = 7.5 Hz, 1.4H), 0.95 (t, J = 7.5 Hz,431.0 yl](6-{[6- 1.6H), 1.08-1.33 (m, 1.6 H), [M + H]⁺(trifluoromethyl)pyridin- 1.34-1.52 (m, 1.4H), 2.55-2.94 (m, 3H),2.95-3.17 (m, 3- 1H), 3.52-3.77 (m, 1H), 4.39 (dd, J = 26.4,yl]oxy}quinolin-2- 11.0 Hz, 1H), 7.62-7.82 (m, 4H), 7.95 (dd, J = 16.4,yl)methanone 8.2 Hz, 1H), 8.13 (dd, J = 9.0, 4.4 Hz, 1H), 8.46 (d, J =8.5 Hz, 1H), 8.70 (t, J = 2.9 Hz, 1H) Example [(3R)-3- ¹H NMR (400 MHz,DMSO-d₆, rotamers) δ DCI m/z 544 (hydroxymethyl)piperazin- ppm 2.40 (s,1H), 2.62 (ddt, J = 28.5, 22.7, 9.7 Hz, 433.0 1-yl](6-{[6- 2.5H),2.74-2.94 (m, 1.5H), [M + H]⁺ (trifluoromethyl)pyridin- 2.95-3.19 (m,1.5H), 3.25 (dt, J = 10.7, 5.4 Hz, 0.5H), 3- 3.35-3.46 (m, 1H), 3.58 (d,J = 13.3 Hz, yl]oxy}quinolin-2- 0.5H), 3.69 (d, J = 11.8 Hz, 0.5H), 4.36(d, J = 12.5 Hz, yl)methanone 0.5H), 4.51 (dd, J = 14.2, 8.9 Hz, 1H),4.74 (t, J = 5.5 Hz, 0.5H), 7.67 (dd, J = 8.5, 2.4 Hz, 1H), 7.71-7.81(m, 3H), 7.96 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.45 (d, J= 8.5 Hz, 1H), 8.70 (dd, J = 4.3, 3.0 Hz, 1H) Example [(3S)-3- ¹H NMR(400 MHz, DMSO-d₆, rotamers) δ DCI m/z 545 (hydroxymethyl)piperazin- ppm2.40 (s, 1H), 2.62 (ddt, J = 28.5, 22.7, 9.7 Hz, 433.0 1-yl](6-{[6-2.5H), 2.74-2.94 (m, 1.5H), [M + H]⁺ (trifluoromethyl)pyridin- 2.95-3.19(m, 1.5H), 3.25 (dt, J = 10.7, 5.4 Hz, 0.5H), 3- 3.35-3.46 (m, 1H), 3.58(d, J = 13.3 Hz, yl]oxy}quinolin-2- 0.5H), 3.69 (d, J = 11.8 Hz, 0.5H),4.36 (d, J = 12.5 Hz, yl)methanone 0.5H), 4.51 (dd, J = 14.2, 8.9 Hz,1H), 4.74 (t, J = 5.5 Hz, 0.5H), 7.67 (dd, J = 8.5, 2.4 Hz, 1H),7.71-7.81 (m, 3H), 7.96 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H),8.45 (d, J = 8.5 Hz, 1H), 8.70 (dd, J = 4.3, 3.0 Hz, 1H) Example[cis-3,4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.71 (d, ESI m/z 546dihydroxypyrrolidin- J = 2.8 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 420.11-yl](6-{[6- 8.16 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), [M +H]⁺ (trifluoromethyl)pyridin- 7.84 (d, J = 8.5 Hz, 1H), 7.81-7.71 (m,3H), 3- 5.03-4.92 (m, 2H), 4.12 (d, J = 3.4 Hz, 1H), yl]oxy}quinolin-2-4.11-3.98 (m, 1H), 3.89 (dd, J = 11.4, 5.7 Hz, yl)methanone 1H),3.71-3.58 (m, 2H), 3.44 (m, 1H). Example N-[2- ¹H NMR (400 MHz, DMSO-d₆)δ ppm 9.14 (t, ESI m/z 547 (trifluoromethoxy)ethyl]- J = 6.0 Hz, 1H),8.64-8.59 (m, 1H), 8.55 (d, J = 8.5 Hz, 446.1 6-{[5- 1H), 8.35-8.28 (m,1H), [M + H]⁺ (trifluoromethyl)pyridin- 8.24-8.16 (m, 2H), 7.94 (d, J =2.6 Hz, 1H), 7.77 (dd, J = 9.1, 2- 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz,1H), yl]oxy}quinoline-2- 4.29 (t, J = 5.6 Hz, 2H), 3.71 (q, J = 5.7 Hz,2H). carboxamide Example [(3R)-3- ¹H NMR (400 MHz, DMSO-d₆₎ 1:1 rotamersδ MS 548 fluoropyrrolidin-1- ppm 8.71 (d, J = 2.4 Hz, 1H), 8.47 (d, J =8.5 Hz, (ESI) yl](6-{[6- 1H), 8.20 (d, J = 9.2 Hz, 0.5H), 8.17 (d, J =9.2 Hz, m/z (trifluoromethyl)pyridin- 0.5H), 7.97 (d, J = 8.5 Hz, 1H),406.1 3- 7.87-7.92 (m, 1H), 7.74-7.80 (m, 3H), 5.46-5.49 (m, [M + H]⁺yl]oxy}quinolin-2- 0.5H), 5.33-5.36 (m, 0.5H), 3.59-4.12 (m, 4H),yl)methanone 2.04-2.27 (m, 2H). Example [(3S)-3- ¹H NMR (400 MHz,DMSO-d₆) 1:1 rotamers δ MS 549 methylpiperazin-1- ppm 8.69-8.70 (m, 1H),8.45 (d, J = 8.5 Hz, (ESI) yl](6-{[6- 1H), 8.13 (d, J = 9.2 Hz, 1H),7.97 (d, J = 8.9 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.71-7.77 (m,2H), 7.67 (d, J = 8.5 Hz, 417.1 3- 1H), 4.36-4.39 (m, 1H), 3.54-3.58 (m,1H), [M + H]⁺ yl]oxy}quinolin-2- 2.97-3.09 (m, 1H), 2.60-2.87 (m, 4H),1.05 (d, yl)methanone J = 6.4 Hz, 1.5H), 0.84 (d, J = 5.8 Hz, 1.5H).Example [(3S)-3- ¹H NMR (400 MHz, DMSO-d₆) 1:1 rotamers δ MS 550fluoropyrrolidin-1- ppm 8.71 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 8.5 Hz,(ESI) yl](6-{[6- 1H), 8.20 (d, J = 9.2 Hz, 0.5H), 8.17 (d, J = 9.2 Hz,m/z (trifluoromethyl)pyridin- 0.5H), 7.97 (d, J = 8.5 Hz, 1H), 406.1 3-7.87-7.92 (m, 1H), 7.74-7.80 (m, 3H), 5.46-5.49 (m, [M + H]⁺yl]oxy}quinolin-2- 0.5H), 5.33-5.36 (m, 0.5H), 3.59-4.12 (m, 4H),yl)methanone 2.04-2.27 (m, 2H). Example N-(3,3,3-trifluoro-2- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.00 (t, MS 551 hydroxypropyl)-6- J = 6.1 Hz,1H), 8.72 (d, J = 2.8 Hz, 1H), 8.54 (d, (ESI) {[6- J = 8.2 Hz, 1H),8.21-8.24 (m, 1H), 8.18 (d, m/z (trifluoromethyl)pyridin- J = 8.2 Hz,1H), 7.99 (d, J = 8.5 Hz, 1H), 446.0 3- 7.77-7.83 (m, 3H), 6.57 (s, 1H),4.28-4.37 (m, 1H), [M + H]⁺ yl]oxy}quinoline-2- 3.68-3.74 (m, 1H),3.49-3.56 (m, 1H). carboxamide Example (3,5- ¹H NMR (400 MHz, DMSO-d₆) δppm 0.84 (d, DCI m/z 552 dimethylpiperazin-1- J = 6.2 Hz, 3H), 1.06 (d,J = 6.2 Hz, 3H), 431.0 yl)(6-{[5- 2.35 (dd, J = 12.2, 10.9 Hz, 2H),2.57-2.70 (m, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 2.76 (ddt, J =8.6, 6.0, 4.4 Hz, 2H), 2- 3.57 (d, J = 12.0 Hz, 1H), 4.37-4.53 (m, 1H),yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 7.63-7.75 (m, 2H),yl)methanone 7.89 (d, J = 2.6 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 8.30(dd, J = 8.7, 2.5 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.59 (dd, J = 1.5,0.8 Hz, 1H) Example [(3S)-3- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCIm/z 553 ethylpiperazin-1- ppm 0.74 (t, J = 7.5 Hz, 1.4H), 0.95 (t, J =7.5 Hz, 431.0 yl](6-{[6- 1.6H), 1.08-1.32 (m, 1H), [M + H]⁺(trifluoromethyl)pyridin- 1.33-1.50 (m, 1H), 2.25-2.43 (m, 1H),2.56-2.93 (m, 3- 3H), 2.93-3.16 (m, 1H), 3.48-3.62 (m,yl]oxy}quinolin-2- 0.6H), 3.64-3.77 (m, 0.4H), 4.30-4.49 (m,yl)methanone 1H), 7.62-7.82 (m, 4H), 7.92-8.01 (m, 1H), 8.06-8.20 (m,1H), 8.45 (d, J = 8.4 Hz, 1H), 8.70 (t, J = 3.1 Hz, 1H) Example[3-(morpholin-4- ¹H NMR (500 MHz, DMSO-d₆ rotamers)δ DCI m/z 554yl)azetidin-1-yl](6- ppm 2.37 (s, 4H), 3.13-3.26 (m, 1H), 3.62 (t, 459.0{[6- J = 4.3 Hz, 4H), 3.88-4.00 (m, 1H), 4.15 (dd, [M + H]⁺(trifluoromethyl)pyridin- J = 10.1, 7.5 Hz, 1H), 4.56 (dd, J = 10.6, 4.9Hz, 3- 1H), 4.77 (dd, J = 10.3, 7.2 Hz, 1H), yl]oxy}quinolin-2-7.70-7.85 (m, 3H), 7.98 (dd, J = 13.1, 8.9 Hz, 1H), yl)methanone 8.04(d, J = 8.6 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H),8.70 (d, J = 2.7 Hz, 1H) Example N-(3,3- ¹H NMR (500 MHz, DMSO-d₆) δ ppmDCI m/z 555 difluorocyclobutyl)- 2.83-3.07 (m, 4H), 4.31-4.48 (m, 1H),424.0 6-{[6- 7.74-7.88 (m, 3H), 7.95-8.02 (m, 1H), 8.14 (d, J = 8.5 Hz,[M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.21-8.29 (m, 1H), 8.52 (d, J =8.6 Hz, 3- 1H), 8.72 (d, J = 2.6 Hz, 1H), 9.41 (d, J = 7.5 Hz,yl]oxy}quinoline-2- 1H) carboxamide Example N-(3-oxocyclobutyl)- ¹H NMR(500 MHz, DMSO-d₆) δ ppm 3.40 (t, DCI m/z 556 6-{[6- J = 7.2 Hz, 4H),4.71 (h, J = 7.2 Hz, 1H), 402.0 (trifluoromethyl)pyridin- 7.74-7.87 (m,3H), 7.98 (t, J = 10.8 Hz, 1H), [M + H]⁺ 3- 8.17 (d, J = 8.5 Hz, 1H),8.24 (dd, J = 14.2, 6.7 Hz, yl]oxy}quinoline-2- 1H), 8.52 (d, J = 8.5Hz, 1H), 8.72 (d, J = 2.6 Hz, carboxamide 1H), 9.51 (d, J = 7.6 Hz, 1H)Example [3-(piperazin-1- ¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 557yl)azetidin-1-yl](6- 8.61-8.57 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H), (ESI){[5- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.18 (d, J = 9.1 Hz, m/z(trifluoromethyl)pyridin- 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.89 (d, J =2.6 Hz, 458.2 2- 1H), 7.72 (dd, J = 9.1, 2.6 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.39 (d, J = 8.7 Hz, 1H), 4.75 (dd, J = 10.1, 7.3 Hz,yl)methanone 1H), 4.52 (dd, J = 10.6, 5.1 Hz, 1H), 4.13 (dd, J = 10.0,7.6 Hz, 1H), 3.93 (dd, J = 10.4, 5.0 Hz, 1H), 3.18-3.10 (m, 1H),2.76-2.66 (m, 4H), 2.27 (br s, 4H). Example 4,7- ¹H NMR (500 MHz, CDCl₃)δ ppm 8.29 (s, MS 558 diazaspiro[2.5]oct-7- 1H), 8.22 (t, J = 7.9 Hz,1H), 8.14 (dd, J = 25.1, (ESI) yl(6-{[5- 9.1 Hz, 1H), 7.92 (dd, J = 8.5,1.6 Hz, m/z (difluoromethyl)pyridin- 1H), 7.75 (dd, J = 8.4, 5.1 Hz,1H), 7.62 (dd, J = 5.6, 411.1 2-yl]oxy}quinolin- 2.4 Hz, 1H), 7.57 (ddd,J = 8.9, 6.0, 2.5 Hz, [M + H]⁺ 2-yl)methanone 1H), 7.14 (dd, J = 8.5,3.3 Hz, 1H), 6.69 (t, J = 55.9 Hz, 1H), 3.94-3.85 (m, 1H), 3.79-3.68 (m,2H), 3.56 (s, 1H), 3.18-3.09 (m, 1H), 3.07-2.98 (m, 1H), 0.82-0.46 (m,4H). Example N-{2-[(3R)-3- 1H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 559hydroxypyrrolidin-1- 8.59-8.47 (m, 2H), 8.29-8.12 (m, 3H), (APCI)yl]-2-oxoethyl}-6- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.7 Hz,m/z {[5- 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.45-4.27 (m, 461.1(trifluoromethyl)pyridin- 1H), 4.24-4.12 (m, 4H), 3.67-3.39 (m, 2H),[M + H]⁺ 2- 2.09-1.77 (m, 2H). yl]oxy}quinoline-2- carboxamide ExampleN-{2-[(3S)-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 560hydroxypyrrolidin-1- 8.59-8.47 (m, 2H), 8.28-8.12 (m, 3H), (APCI)yl]-2-oxoethyl}-6- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.7 Hz,m/z {[5- 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.36 (d, J = 36.6 Hz, 461.1(trifluoromethyl)pyridin- 1H), 4.18 (d, J = 15.8 Hz, 2H), [M + H]⁺ 2-3.68-3.32 (m, 4H), 2.09-1.76 (m, 2H). yl]oxy}quinoline-2- carboxamideExample N-[2-(3-hydroxy-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 561methylpyrrolidin-1- 8.59-8.47 (m, 2H), 8.29-8.12 (m, 3H), (APCI)yl)-2-oxoethyl]-6- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.6 Hz,m/z {[5- 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.28-4.08 (m, 475.1(trifluoromethyl)pyridin- 2H), 3.71-3.37 (m, 3H), 3.20 (d, J = 12.1 Hz,[M + H]⁺ 2- 1H), 2.00-1.70 (m, 2H), 1.35 (d, J = 7.3 Hz,yl]oxy}quinoline-2- 3H). carboxamide Example N-{2-[(3S,4S)-3,4- ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ ppm MS 562 dihydroxypyrrolidin- 8.59-8.48 (m,2H), 8.28-8.13 (m, 3H), (APCI) 1-yl]-2-oxoethyl}-6- 7.86 (d, J = 2.6 Hz,1H), 7.73 (dd, J = 9.1, 2.7 Hz, m/z {[5- 1H), 7.35 (d, J = 8.7 Hz, 1H),4.18 (d, J = 1.6 Hz, 477.1 (trifluoromethyl)pyridin- 2H), 4.08 (s, 1H),3.99 (s, 1H), [M + H]⁺ 2- 3.79-3.67 (m, 1H), 3.60-3.47 (m, 1H),3.46-3.36 (m, yl]oxy}quinoline-2- 2H). carboxamide ExampleN-{2-[(3R,4R)-3,4- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 563dihydroxypyrrolidin- 8.59-8.47 (m, 2H), 8.29-8.12 (m, 3H), (APCI)1-yl]-2-oxoethyl}-6- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.6Hz, m/z {[5- 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.18 (d, J = 1.7 Hz, 477.1(trifluoromethyl)pyridin- 2H), 4.08 (s, 1H), 3.99 (s, 1H), [M + H]⁺ 2-3.79-3.67 (m, 1H), 3.60-3.47 (m, 1H), 3.46-3.36 (m, yl]oxy}quinoline-2-2H). carboxamide Example N-{2-[(2S,4R)-4- ¹H NMR (400 MHz, DMSO-d₆/D₂O)δ ppm MS 564 hydroxy-2- 8.58-8.50 (m, 2H), 8.26-8.15 (m, 3H), (APCI)(hydroxymethyl)pyrrolidin- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1,2.6 Hz, m/z 1-yl]-2- 1H), 7.35 (d, J = 8.7 Hz, 1H), 4.46-4.06 (m, 491.1oxoethyl}-6-{[5- 4H), 3.68-3.36 (m, 4H), 2.11-1.98 (m, 1H), [M + H]⁺(trifluoromethyl)pyridin- 1.98-1.82 (m, 1H). 2- yl]oxy}quinoline-2-carboxamide Example N-[2-(3,3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS565 difluoropyrrolidin-1- 8.59-8.48 (m, 2H), 8.28-8.12 (m, 3H), (APCI)yl)-2-oxoethyl]-6- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.7 Hz,m/z {[5- 1H), 7.35 (d, J = 8.7 Hz, 1H), 4.22 (s, 2H), 481.0(trifluoromethyl)pyridin- 4.01 (s, 1H), 3.89-3.54 (m, 3H), [M + H]⁺ 2-2.49-2.33 (m, 2H). yl]oxy}quinoline-2- carboxamide Example N-[2-(3- ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 566 hydroxyazetidin-1- 8.59-8.47 (m,2H), 8.29-8.11 (m, 3H), (APCI) yl)-2-oxoethyl]-6- 7.86 (d, J = 2.6 Hz,1H), 7.72 (dd, J = 9.1, 2.7 Hz, m/z {[5- 1H), 7.34 (d, J = 8.6 Hz, 1H),4.60-4.47 (m, 447.1 (trifluoromethyl)pyridin- 1H), 4.19 (s, 2H), 4.03(s, 2H), 3.99-3.54 (m, [M + H]⁺ 2- 2H). yl]oxy}quinoline-2- carboxamideExample N-[2-(3-hydroxy-3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 567methylazetidin-1-yl)- 8.59-8.47 (m, 2H), 8.29-8.11 (m, 3H), (APCI)2-oxoethyl]-6-{[5- 7.86 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 9.1, 2.7 Hz,m/z (trifluoromethyl)pyridin- 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.20-3.94(m, 461.1 2- 4H), 3.94-3.68 (m, 2H), 1.43 (s, 3H). [M + H]⁺yl]oxy}quinoline-2- carboxamide Example N-[2-(1,1-dioxido- ¹H NMR (400MHz, DMSO-d₆/D₂O) δ ppm MS 568 1,3-thiazolidin-3-yl)- 8.59-8.48 (m, 2H),8.29-8.12 (m, 3H), (APCI) 2-oxoethyl]-6-{[5- 7.86 (d, J = 2.6 Hz, 1H),7.73 (dd, J = 9.1, 2.7 Hz, m/z (trifluoromethyl)pyridin- 1H), 7.35 (d, J= 8.7 Hz, 1H), 4.66 (s, 2H), 495.0 2- 4.31 (s, 2H), 4.07 (s, 2H), 3.47(s, 2H). [M + H]⁺ yl]oxy}quinoline-2- carboxamide Example N-[2-(3- ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 569 methoxyazetidin-1- 8.59-8.48 (m,2H), 8.27-8.11 (m, 3H), (APCI) yl)-2-oxoethyl]-6- 7.86 (d, J = 2.6 Hz,1H), 7.72 (dd, J = 9.1, 2.7 Hz, m/z {[5- 1H), 7.34 (d, J = 8.7 Hz, 1H),4.41-4.24 (m, 461.1 (trifluoromethyl)pyridin- 2H), 4.24-3.61 (m, 5H),3.25 (s, 3H). [M + H]⁺ 2- yl]oxy}quinoline-2- carboxamide ExampleN-{2-[(2R)-2- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 570(hydroxymethyl)pyrrolidin- 8.59-8.47 (m, 2H), 8.29-8.12 (m, 3H), (APCI)1-yl]-2- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.7 Hz, m/zoxoethyl}-6-{[5- 1H), 7.35 (d, J = 8.7 Hz, 1H), 4.37-4.11 (m, 475.1(trifluoromethyl)pyridin- 2H), 4.06 (s, 1H), 3.58-3.39 (m, 4H), [M + H]⁺2- 2.02-1.81 (m, 4H). yl]oxy}quinoline-2- carboxamide ExampleN-[2-(azetidin-1-yl)- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppm MS 5712-oxoethyl]-6-{[5- 8.59-8.47 (m, 2H), 8.29-8.11 (m, 3H), (APCI)(trifluoromethyl)pyridin- 7.86 (d, J = 2.5 Hz, 1H), 7.72 (dd, J = 9.1,2.6 Hz, m/z 2- 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.36-4.08 (m, 431.1yl]oxy}quinoline-2- 2H), 4.08-3.92 (m, 3H), 2.36-2.20 (m, 2H). [M + H]⁺carboxamide Example N-[2-oxo-2-(3- ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ ppmMS 572 oxopyrrolidin-1- 8.59-8.48 (m, 2H), 8.27-8.13 (m, 3H), (APCI)yl)ethyl]-6-{[5- 7.86 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 9.2, 2.6 Hz,m/z (trifluoromethyl)pyridin- 1H), 7.35 (d, J = 8.7 Hz, 1H), 4.26 (s,2H), 459.1 2- 4.12-3.67 (m, 4H), 2.69 (s, 2H). [M + H]⁺yl]oxy}quinoline-2- carboxamide Example N-[2-(3- ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ ppm MS 573 fluoropyrrolidin-1- 8.59-8.48 (m, 2H),8.28-8.14 (m, 3H), (APCI) yl)-2-oxoethyl]-6- 7.86 (d, J = 2.6 Hz, 1H),7.73 (dd, J = 9.2, 2.7 Hz, m/z {[5- 1H), 7.35 (d, J = 8.7 Hz, 1H),5.53-5.23 (m, 463.1 (trifluoromethyl)pyridin- 1H), 4.29-4.14 (m, 2H),3.88-3.39 (m, 4H), [M + H]⁺ 2- 2.39-1.97 (m, 2H). yl]oxy}quinoline-2-carboxamide Example N-[3-(morpholin-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppmDCI m/z 574 yl)cyclobutyl]-6-{[6- 1.97-2.14 (m, 2H), 2.30 (s, 4H),2.35-2.46 (m, 473.0 (trifluoromethyl)pyridin- 2H), 3.54-3.65 (m, 4H),4.15-4.31 (m, 1H), [M + H]⁺ 3- 7.74-7.85 (m, 3H), 7.98 (d, J = 8.7 Hz,1H), yl]oxy}quinoline-2- 8.12 (d, J = 8.5 Hz, 1H), 8.20-8.29 (m, 1H),carboxamide 8.49 (d, J = 8.5 Hz, 1H), 8.71 (d, J = 2.7 Hz, 1H), 9.02 (d,J = 8.4 Hz, 1H) Example (6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z575 (difluoromethyl)pyridin- 2.01-2.32 (m, 2H), 3.56-4.19 (m, 4H), 5.36(d, J = 15.9 Hz, 388.0 2-yl]oxy}quinolin- 0.5H), 5.46 (d, J = 15.6 Hz,0.5H), [M + H]⁺ 2-yl)[(3R)-3- 7.13 (t, J = 55.3 Hz, 1H), 7.33 (d, J =8.6 Hz, fluoropyrrolidin-1- 1H), 7.70 (dd, J = 9.1, 2.0 Hz, 1H),yl]methanone 7.81-7.95 (m, 2H), 8.15 (t, J = 7.9 Hz, 2H), 8.40 (s, 1H),8.48 (d, J = 8.6 Hz, 1H) Example (6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppmDCI m/z 576 (difluoromethyl)pyridin- 2.01-2.32 (m, 2H), 3.56-4.19 (m,4H), 5.36 (d, J = 15.9 Hz, 388.0 2-yl]oxy}quinolin- 0.5H), 5.46 (d, J =15.6 Hz, 0.5H), [M + H]⁺ 2-yl)[(3S)-3- 7.13 (t, J = 55.3 Hz, 1H), 7.33(d, J = 8.6 Hz, fluoropyrrolidin-1- 1H), 7.70 (dd, J = 9.1, 2.0 Hz, 1H),yl]methanone 7.81-7.95 (m, 2H), 8.15 (t, J = 7.9 Hz, 2H), 8.40 (s, 1H),8.48 (d, J = 8.6 Hz, 1H) Example N-(methylsulfonyl)- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.95 (s, DCI m/z 577 6-{[5- 3H), 7.39 (t, J = 9.7 Hz,1H), 7.67 (dd, J = 9.1, 412.0 (trifluoromethyl)pyridin- 2.7 Hz, 1H),7.83 (d, J = 2.6 Hz, 1H), 8.19 (t, J = 7.9 Hz, [M + H]⁺ 2- 1H),8.25-8.42 (m, 3H), 8.60 (dd, J = 1.6, yl]oxy}quinoline-2- 0.8 Hz, 1H)carboxamide Example N-(3-hydroxy-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29(s, DCI m/z 578 methylcyclobutyl)-6- 3H), 2.16-2.30 (m, 2H), 2.30-2.44(m, 2H), 418.0 {[6- 4.00-4.16 (m, 1H), 4.99 (s, 1H), [M + H]⁺(trifluoromethyl)pyridin- 7.75-7.88 (m, 3H), 7.98 (d, J = 8.7 Hz, 1H),8.13 (d, J = 8.5 Hz, 3- 1H), 8.22-8.29 (m, 1H), 8.50 (d, J = 8.5 Hz,yl]oxy}quinoline-2- 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.85 (d, J = 7.9 Hz,carboxamide 1H) Example N-[1- ¹H NMR (400 MHz, CDCl₃) δ ppm MS 579(dimethylamino)-1- 9.08-9.01 (m, 1H), 8.46 (d, J = 3.0 Hz, 1H), (ESI)oxopropan-2-yl]-6- 8.32-8.19 (m, 3H), 7.97 (dd, J = 8.6, 2.5 Hz, 1H),m/z {[5- 7.64 (d, J = 2.6 Hz, 1H), 7.57 (dd, J = 9.1, 2.6 Hz, 433.0(trifluoromethyl)pyridin- 1H), 7.14 (d, J = 8.6 Hz, 1H), 5.25-5.13 (m,[M + H]⁺ 2- 1H), 3.17 (s, 3H), 3.04 (s, 3H), 1.52 (d, J = 6.8 Hz,yl]oxy}quinoline-2- 3H). carboxamide Example N-(3,3- ¹H NMR (400 MHz,DMSO-d₆) δ ppm DCI m/z 580 difluorocyclobutyl)- 2.86-3.09 (m, 4H),4.32-4.52 (m, 1H), 7.13 (t, J = 55.3 Hz, 406.0 6-{[5- 1H), 7.34 (d, J =8.6 Hz, 1H), [M + H]⁺ (difluoromethyl)pyridin- 7.74 (dd, J = 9.1, 2.7Hz, 1H), 7.89 (d, J = 2.6 Hz, 2- 1H), 8.08-8.19 (m, 2H), 8.22 (d, J =9.1 Hz, yl]oxy}quinoline-2- 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.53 (d, J =8.4 Hz, carboxamide 1H), 9.40 (d, J = 7.5 Hz, 1H) Example [(3R)-3- ¹HNMR (400 MHz, DMSO-d₆) δ ppm MS 581 hydroxypiperidin-1- 8.59 (dd, J =1.7, 0.8 Hz, 1H), 8.47 (dd, J = 8.5, 2.2 Hz, (ESI) yl](6-{[5- 1H), 8.30(dd, J = 8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.10 (dd, J =9.1, 4.4 Hz, 1H), 7.89 (dd, J = 2.5, 2.5 Hz, 418.1 2- 1H), 7.76-7.63 (m,2H), 7.39 (d, J = 8.7 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 5.04-4.81 (m,1H), 4.29-3.90 (m, 1H), yl)methanone 3.66-3.44 (m, 2H), 3.30-2.88 (m,2H), 1.97-1.58 (m, 2H), 1.58-1.36 (m, 2H) Example [(3S)-3- ¹H NMR (400MHz, DMSO-d₆) δ ppm MS 582 hydroxypiperidin-1- 8.59 (dd, J = 1.5, 0.7Hz, 1H), 8.47 (dd, J = 8.5, 2.4 Hz, (ESI) yl](6-{[5- 1H), 8.30 (dd, J =8.7, 2.6 Hz, 1H), m/z (trifluoromethyl)pyridin- 8.11 (dd, J = 9.1, 4.6Hz, 1H), 7.89 (dd, J = 2.5, 2.5 Hz, 418.1 2- 1H), 7.76-7.63 (m, 2H),7.39 (d, J = 8.8 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 5.06-4.81 (m, 1H),4.32-3.90 (m, 1H), yl)methanone 3.66-3.44 (m, 2H), 3.30-2.88 (m, 2H),1.97-1.58 (m, 2H), 1.54-1.39 (m, 2H) Example [(3R,4R)-4-amino-3- ¹H NMR(400 MHz, CDCl₃) δ ppm 8.44 (bs, MS 583 fluoropiperidin-1- 1H), 8.23(dd, J = 8.5, 2.8 Hz, 1H), 8.15 (t, J = 8.4 Hz, (ESI) yl](6-{[5- 1H),7.97 (dd, J = 8.6, 2.5 Hz, 1H), m/z (trifluoromethyl)pyridin- 7.76 (dd,J = 11.5, 8.4 Hz, 1H), 7.63 (bs, 1H), 435.1 2- 7.62-7.54 (m, 1H), 7.15(d, J = 8.6 Hz, 1H), [M + H]⁺ yl]oxy}quinolin-2- 5.03-4.09 (m, 3H),3.37-2.96 (m, 3H), yl)methanone 1.71-1.56 (m, 1H), 0.91-0.80 (m, 1H).Example N-[(3R,4R)-3- ¹H NMR (500 MHz, CDCl₃) δ ppm 8.45 (bs, MS 584fluoropiperidin-4-yl]- 1H), 8.37-8.30 (m, 2H), 8.28 (d, J = 8.5 Hz,(ESI) 6-{[5- 1H), 8.19 (d, J = 9.1 Hz, 1H), 7.98 (dd, J = 8.7, m/z(trifluoromethyl)pyridin- 2.4 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.60(dd, 435.1 2- J = 9.1, 2.5 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), [M + H]⁺yl]oxy}quinoline-2- 4.67-4.49 (m, 1H), 4.39-4.27 (m, 1H), carboxamide3.49-3.40 (m, 1H), 3.14-3.06 (m, 1H), 2.92-2.75 (m, 2H), 2.32-2.23 (m,1H), 1.69 (qd, J = 10.6, 4.0 Hz, 1H). Example (6-{[5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm DCI m/z 585 (difluoromethyl)pyridin- 2.66-3.06 (m, 4H),3.07-3.29 (m, 3H), 3.76 (d, J = 13.7 Hz, 415.0 2-yl]oxy}quinolin- 0.5H),3.83 (t, J = 12.4 Hz, 0.5H), [M + H]⁺ 2-yl)[(3S)-3- 4.43 (d, J = 12.9Hz, 0.5H), 4.54 (d, J = 12.8 Hz, (hydroxymethyl)piperazin- 0.5H), 4.91(d, J = 88.7 Hz, 1H), 7.12 (t, J = 55.3 Hz, 1-yl]methanone 1H), 7.32 (d,J = 8.6 Hz, 1H), 7.63-7.77 (m, 2H), 7.85 (d, J = 2.6 Hz, 1H), 8.04-8.19(m, 2H), 8.39 (s, 1H), 8.49 (t, J = 8.2 Hz, 1H) Example {3-[(3S)-3- ¹HNMR (400 MHz, DMSO-d₆, rotamers) δ MS 586 fluoropyrrolidin-1- ppm8.61-8.57 (m, 1H), 8.48 (d, J = 8.5 Hz, (ESI) yl]azetidin-1-yl}(6- 1H),8.30 (dd, J = 8.7, 2.6 Hz, 1H), 8.18 (dd, J = 9.1, m/z {[5- 2.7 Hz, 1H),8.04 (d, J = 8.6 Hz, 1H), 461.1 (trifluoromethyl)pyridin- 7.89 (d, J =2.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.7 Hz, [M + H]⁺ 2- 1H), 7.39 (d, J =8.7 Hz, 1H), yl]oxy}quinolin-2- 5.35-5.25 (m, 0.5H), 5.20-5.11 (m,0.5H), 4.80 (dd, J = 10.2, yl)methanone 7.5 Hz, 1H), 4.61-4.53 (m, 1H),4.19 (dd, J = 10.1, 7.4 Hz, 1H), 4.02-3.93 (m, 1H), 3.49-3.40 (m, 1H),2.94-2.78 (m, 2H), 2.72 (dd, J = 11.5, 4.9 Hz, 0.5H), 2.64 (dd, J =11.5, 4.9 Hz, 0.5H), 2.44-2.35 (m, 1H), 2.24-2.07 (m, 1H), 2.00-1.83 (m,1H). Example N-(1-methyl-2- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.69 (d, J =5.8 Hz, MS 587 oxopyrrolidin-3-yl)- 1H), 8.46 (d, J = 3.0 Hz, 1H), (ESI)6-{[5- 8.27 (q, J = 8.5 Hz, 2H), 8.17 (d, J = 9.1 Hz, 1H), m/z(trifluoromethyl)pyridin- 7.98 (dd, J = 8.6, 2.5 Hz, 1H), 7.65 (d, J =2.5 Hz, 431.1 2- 1H), 7.57 (dd, J = 9.1, 2.5 Hz, 1H), [M + H]⁺yl]oxy}quinoline-2- 7.14 (d, J = 8.6 Hz, 1H), 4.66 (dd, J = 15.4, 9.1Hz, carboxamide 1H), 3.54-3.37 (m, 2H), 2.98 (s, 3H), 2.91-2.78 (m, 1H),2.08 (dq, J = 12.7, 9.6 Hz, 1H). Example [(3R)-3- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.59 (s, MS 588 methoxypyrrolidin-1- 1H), 8.47 (dd, J =8.5, 1.9 Hz, 1H), 8.30 (dd, J = 8.7, (ESI) yl](6-{[5- 2.5 Hz, 1H), 8.14(d, J = 9.1 Hz, 1H), m/z (trifluoromethyl)pyridin- 7.91-7.89 (m, 1H),7.86 (dd, J = 8.5, 5.5 Hz, 418.1 2- 1H), 7.72 (ddd, J = 9.1, 2.3, 2.3Hz, 1H), [M + H]⁺ yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 4.08-3.97(m, 1H), yl)methanone 3.95-3.77 (m, 2H), 3.72-3.52 (m, 2H), 3.30-3.21(m, 3H), 2.10-1.92 (m, 2H) Example [(3S)-3- ¹H NMR (400 MHz, DMSO-d₆) δppm 8.59 (s, MS 589 methoxypyrrolidin-1- 1H), 8.47 (dd, J = 8.5, 1.0 Hz,1H), 8.30 (dd, J = 8.7, (ESI) yl](6-{[5- 2.5 Hz, 1H), 8.14 (d, J = 9.1Hz, 1H), m/z (trifluoromethyl)pyridin- 7.91-7.88 (m, 1H), 7.86 (dd, J =8.5, 5.5 Hz, 418.1 2- 1H), 7.72 (ddd, J = 9.1, 2.3, 2.3 Hz, 1H), [M +H]⁺ yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 4.08-3.97 (m, 1H),yl)methanone 3.95-3.77 (m, 2H), 3.72-3.52 (m, 2H), 3.30-3.21 (m, 3H),2.10-1.92 (m, 2H) Example N-(2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.78 (t,MS 590 methoxypropyl)-6- J = 6.1 Hz, 1H), 8.60-8.61 (m, 1H), 8.55 (d,(ESI) {[5- J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), m/z(trifluoromethyl)pyridin- 8.18-8.22 (m, 2H), 7.93 (d, J = 2.8 Hz, 1H),406.1 2- 7.76 (dd, J = 9.2, 2.4 Hz, 1H), 7.40 (d, J = 8.5 Hz, [M + H]⁺yl]oxy}quinoline-2- 1H), 3.55-3.62 (m, 1H), 3.36-3.50 (m, 2H),carboxamide 3.31 (s, 3H), 1.13 (d, J = 6.1 Hz, 3H). Example N-[(1- ¹HNMR (400 MHz, DMSO-d₆) δ ppm MS 591 methoxycyclobutyl)methyl]- 8.61-8.62(m, 1H), 8.52-8.57 (m, 2H), 8.31 (dd, (ESI) 6-{[5- J = 8.7, 2.6 Hz, 1H),8.20-8.23 (m, 2H), 7.94 (d, m/z (trifluoromethyl)pyridin- J = 2.4 Hz,1H), 7.75 (dd, J = 9.2, 2.8 Hz, 1H), 432.1 2- 7.40 (d, J = 8.9 Hz, 1H),3.66 (d, J = 6.1 Hz, 2H), [M + H]⁺ yl]oxy}quinoline-2- 3.20 (s, 3H),2.04-2.12 (m, 2H), 1.92-1.98 (m, carboxamide 2H), 1.60-1.75 (m, 2H).Example 6-{[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.41 (d, DCI m/z 592(difluoromethyl)pyridin- J = 7.1 Hz, 4H), 4.63-4.81 (m, 1H), 7.13 (t, J= 55.3 Hz, 384.0 2-yl]oxy}-N-(3- 1H), 7.34 (d, J = 8.6 Hz, 1H), [M + H]⁺oxocyclobutyl)quinoline- 7.74 (dd, J = 9.1, 2.6 Hz, 1H), 7.89 (d, J =2.6 Hz, 2-carboxamide 1H), 8.17 (ddd, J = 13.3, 10.9, 5.8 Hz, 3H), 8.41(d, J = 1.6 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 9.51 (d, J = 7.6 Hz, 1H)Example [(3S)-3- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCI m/z 593(methoxymethyl)piperazin- ppm 2.56-3.26 (m, 8H), 3.32 (d, J = 10.9 Hz,447.0 1-yl](6-{[5- 3H), 3.64 (dd, J = 27.4, 11.9 Hz, 1H), 4.34 (d, [M +H]⁺ (trifluoromethyl)pyridin- J = 12.6 Hz, 0.5H), 4.42-4.52 (d, J = 12.6Hz,, 2- 0.5H), 7.39 (dd, J = 8.7, 3.7 Hz, 1H), yl]oxy}quinolin-2-7.63-7.77 (m, 2H), 7.89 (t, J = 2.2 Hz, 1H), yl)methanone 8.11 (dd, J =9.1, 2.0 Hz, 1H), 8.30 (dd, J = 8.7, 2.2 Hz, 1H), 8.48 (d, J = 8.5 Hz,1H), 8.59 (s, 1H) Example [3- ¹H NMR (500 MHz, CDCl₃) δ ppm 8.45 (d, J =3.9 Hz, MS 594 (difluoromethyl)piperazin- 1H), 8.24 (d, J = 8.5 Hz, 1H),(ESI) 1-yl](6-{[5- 8.16 (d, J = 9.1 Hz, 1H), 7.98 (dd, J = 8.6, 2.5 Hz,m/z (trifluoromethyl)pyridin- 1H), 7.79 (dd, J = 20.5, 8.5 Hz, 1H), 7.64(d, J = 2.5 Hz, 453.1 2- 1H), 7.58 (dd, J = 9.1, 2.6 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.15 (d, J = 8.6 Hz, 1H), 5.76 (tdd, J = 56.1,yl)methanone 13.8, 4.5 Hz, 1H), 4.64 (dd, J = 117.7, 13.1 Hz, 1H), 4.21(dd, J = 114.0, 11.4 Hz, 1H), 3.41-3.16 (m, 3H), 3.11-2.89 (m, 2H).Example N-(3-cyanopropyl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (t,ESI m/z 595 {[5- J = 6.2 Hz, 1H), 8.61 (s, 1H), 8.53 (d, J = 8.4 Hz,401.2 (trifluoromethyl)pyridin- 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H),8.18 (t, [M + H]⁺ 2- J = 9.2 Hz, 2H), 7.93 (d, J = 2.6 Hz, 1H),yl]oxy}quinoline-2- 7.76 (dd, J = 9.1, 2.6 Hz, 1H), 7.40 (d, J = 8.7 Hz,carboxamide 1H), 3.46 (dd, J = 13.2, 6.7 Hz, 2H), 2.53 (m, 2H),2.01-1.84 (m, 2H). Example N-cyclobutyl-6-{[5- ¹H NMR (500 MHz, DMSO-d₆)δ ppm 9.03 (d, MS 596 (trifluoromethyl)pyridin- J = 8.4 Hz, 1H),8.63-8.59 (m, 1H), 8.52 (d, J = 8.4 Hz, (ESI) 2- 1H), 8.31 (dd, J = 8.7,2.5 Hz, 1H), m/z yl]oxy}quinoline-2- 8.23 (d, J = 9.1 Hz, 1H), 8.14 (d,J = 8.5 Hz, 388.1 carboxamide 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.75 (dd, J= 9.1, [M + H]⁺ 2.6 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 4.57-4.46 (m,1H), 2.28-2.20 (m, 4H), 1.75-1.65 (m, 2H). Example azetidin-1-yl(6-{[5-¹H NMR (400 MHz, DMSO-d₆) δ ppm MS 597 (trifluoromethyl)pyridin-8.61-8.56 (m, 1H), 8.47 (d, J = 8.5 Hz, 1H), (ESI) 2- 8.30 (dd, J = 8.8,2.5 Hz, 1H), 8.13 (d, J = 9.1 Hz, m/z yl]oxy}quinolin-2- 1H), 8.03 (d, J= 8.5 Hz, 1H), 7.88 (d, J = 2.6 Hz, 374.1 yl)methanone 1H), 7.71 (dd, J= 9.1, 2.7 Hz, 1H), [M + H]⁺ 7.39 (d, J = 8.6 Hz, 1H), 4.79-4.70 (m,2H), 4.18-4.09 (m, 2H), 2.39-2.28 (m, 2H). Example [2- ¹H NMR (400 MHz,DMSO-d_(6,) rotamers) δ MS 598 (trifluoromethyl)piperazin- ppm 8.58 (s,1H), 8.52 (d, J = 8.5 Hz, 1H), (ESI) 1-yl](6-{[5- 8.30 (dd, J = 8.8, 2.5Hz, 1H), 8.17-8.09 (m, m/z (trifluoromethyl)pyridin- 1H), 7.91 (d, J =2.6 Hz, 1H), 7.79-7.69 (m, 471.1 2- 2H), 7.43-7.37 (m, 1H), 5.26-5.08(m, 1H), [M + H]⁺ yl]oxy}quinolin-2- 4.34 (d, J = 14.0 Hz, 0.4H), 3.59(d, J = 12.6 Hz, yl)methanone 0.6H), 3.24 (d, J = 13.8 Hz, 0.6H),3.15-2.91 (m, 2H), 2.87-2.55 (m, 2.4H). Example N-(3- ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.98 (t, 599 methoxypropyl)-6- J = 5.9 Hz, 1H), 8.61 (dd,J = 1.6, 0.7 Hz, 1H), {[5- 8.53 (d, J = 8.4 Hz, 1H), 8.31 (dd, J = 8.7,2.5 Hz, (trifluoromethyl)pyridin- 1H), 8.18 (t, J = 9.0 Hz, 2H), 7.93(d, J = 2.6 Hz, 2- 1H), 7.75 (dd, J = 9.1, 2.7 Hz, 1H),yl]oxy}quinoline-2- 7.40 (d, J = 8.7 Hz, 1H), 3.49-3.38 (m, 4H),carboxamide 3.28 (s, 3H), 1.84 (p, J = 6.5 Hz, 2H). ExampleN-(thietan-3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.11 (t, 600ylmethyl)-6-{[5- J = 6.1 Hz, 1H), 8.61 (d, J = 3.0 Hz, 1H),(trifluoromethyl)pyridin- 8.53 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7,2.6 Hz, 2- 1H), 8.23-8.14 (m, 2H), 7.93 (d, J = 2.6 Hz,yl]oxy}quinoline-2- 1H), 7.76 (dd, J = 9.1, 2.6 Hz, 1H), 7.40 (d, J =8.6 Hz, carboxamide 1H), 3.61-3.42 (m, 3H), 3.19 (t, J = 8.6 Hz, 2H),3.05 (dd, J = 9.1, 6.4 Hz, 2H). Example N-[(1-oxidothietan-3- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 601 yl)methyl]-6-{[5- 9.29-9.17 (m, 1H), 8.61(dd, J = 2.6, 1.3 Hz, 1H), (trifluoromethyl)pyridin- 8.54 (d, J = 8.5Hz, 1H), 8.35-8.28 (m, 1H), 2- 8.24-8.15 (m, 2H), 7.94 (d, J = 2.6 Hz,1H), yl]oxy}quinoline-2- 7.76 (dd, J = 9.1, 2.6 Hz, 1H), 7.41 (d, J =8.6 Hz, carboxamide 1H), 3.72-3.50 (m, J = 6.2 Hz, 4H), 3.26-2.94 (m,3H). Example N-[(1,1- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.36 (t, 602dioxidothietan-3- J = 6.2 Hz, 1H), 8.64-8.59 (m, 1H), 8.54 (d, J = 8.5Hz, yl)methyl]-6-{[5- 1H), 8.32 (dd, J = 8.7, 2.6 Hz, 1H),(trifluoromethyl)pyridin- 8.19 (t, J = 8.4 Hz, 2H), 7.94 (d, J = 2.6 Hz,2- 1H), 7.77 (dd, J = 9.0, 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz,yl]oxy}quinoline-2- 1H), 4.32-4.23 (m, 2H), carboxamide 4.10-3.99 (m,2H), 3.64 (t, J = 6.7 Hz, 2H), 2.93-2.82 (m, 1H). Example [(2R)-2- ¹HNMR (500 MHz, DMSO-d₆, rotamers) δ MS 603 (difluoromethyl)piperazin- ppm8.59 (s, 1H), 8.50 (d, J = 8.5 Hz, 1H), (ESI) 1-yl](6-{[5- 8.30 (dd, J =8.7, 2.5 Hz, 1H), 8.12 (t, J = 8.9 Hz, m/z (trifluoromethyl)pyridin-1H), 7.90 (d, J = 2.6 Hz, 1H), 453.1 2- 7.74-7.71 (m, 1H), 7.69 (dd, J =8.5, 7.0 Hz, 1H), [M + H]⁺ yl]oxy}quinolin-2- 7.40 (dd, J = 8.7, 3.7 Hz,1H), 6.55 (tdd, J = 57.0, yl)methanone 37.5, 6.7 Hz, 1H), 4.82-4.74 (m,0.5H), 4.43-4.34 (m, 0.5H), 4.35-4.27 (m, 0.5H), 3.56 (d, J = 13.3 Hz,0.5H), 3.39-3.34 (m, 0.5H), 3.16 (d, J = 13.1 Hz, 0.5H), 3.09-2.93 (m,2H), 2.87-2.77 (m, 1H), 2.76-2.68 (m, 0.5H), 2.63-2.55 (m, 1.5H).Example N-(3- ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ DCI m/z 604fluorocyclobutyl)-6- ppm 2.51-2.83 (m, 4H), 4.08 (dt, J = 16.0, 406.0{[5- 8.1 Hz, 0.4H), 4.60-4.88 (m, 0.8H), 4.97 (p, J = 6.9 Hz, [M + H]⁺(trifluoromethyl)pyridin- 0.2H), 5.27 (tt, J = 6.4, 3.2 Hz, 2- 0.3H),5.41 (tt, J = 6.2, 3.2 Hz, 0.3H), 7.41 (d, yl]oxy}quinoline-2- J = 8.7Hz, 1H), 7.72-7.81 (m, 1H), 7.92 (d, J = 2.6 Hz, carboxamide 1H), 8.15(dd, J = 8.5, 2.4 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 8.31 (dd, J = 8.7,2.5 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.61 (s, 1H), 9.23 (d, J = 7.4Hz, 1H) Example N-[2-(2-oxo-1,3- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08(t, ESI m/z 605 oxazolidin-3- J = 6.1 Hz, 1H), 8.61 (d, J = 2.8 Hz, 1H),447.1 yl)ethyl]-6-{[5- 8.54 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.22-8.14 (m, 2H), 7.93 (d,J = 2.6 Hz, 2- 1H), 7.76 (dd, J = 9.1, 2.6 Hz, 1H), 7.40 (d, J = 8.6 Hz,yl]oxy}quinoline-2- 1H), 4.24 (d, J = 15.8 Hz, 2H), 3.66 (t, carboxamideJ = 7.9 Hz, 2H), 3.55 (q, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H).Example N-[2-(pyridin-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.12 (t, ESIm/z 606 yl)ethyl]-6-{[5- J = 6.0 Hz, 1H), 8.63-8.58 (m, 1H), 439.1(trifluoromethyl)pyridin- 8.58-8.50 (m, 2H), 8.31 (dd, J = 8.6, 2.6 Hz,1H), [M + H]⁺ 2- 8.21-8.14 (m, 2H), 7.92 (d, J = 2.6 Hz, 1H),yl]oxy}quinoline-2- 7.78-7.68 (m, 2H), 7.40 (d, J = 8.6 Hz, 1H),carboxamide 7.33 (d, J = 7.8 Hz, 1H), 7.25 (ddd, J = 7.5, 4.8, 1.2 Hz,1H), 3.75 (q, J = 6.8 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H). ExampleN-[3-(pyridin-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.99 (t, ESI m/z 607yl)propyl]-6-{[5- J = 6.1 Hz, 1H), 8.63-8.59 (m, 1H), 453.1(trifluoromethyl)pyridin- 8.55-8.46 (m, 2H), 8.34-8.28 (m, 1H), [M + H]⁺2- 8.23-8.14 (m, 2H), 7.92 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.1,yl]oxy}quinoline-2- 2.6 Hz, 1H), 7.69 (td, J = 7.6, 1.9 Hz, 1H),carboxamide 7.40 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.19(ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 3.43 (q, J = 6.7 Hz, 2H), 2.82 (t, J =7.6 Hz, 2H), 2.07-1.94 (m, 2H). Example N-[3-(2- ¹H NMR (400 MHz,DMSO-d₆) δ ppm ESI m/z 608 oxopyrrolidin-1- 9.03-8.96 (m, 1H), 8.61 (dt,J = 2.2, 1.1 Hz, 1H), 459.1 yl)propyl]-6-{[5- 8.53 (d, J = 8.5 Hz, 1H),8.34-8.28 (m, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 8.21-8.14 (m, 2H),7.93 (d, J = 2.6 Hz, 1H), 2- 7.76 (dd, J = 9.1, 2.6 Hz, 1H), 7.40 (d, J= 8.6 Hz, yl]oxy}quinoline-2- 1H), 3.39-3.24 (m, 6H), 2.24 (t, J = 8.0Hz, carboxamide 2H), 2.00-1.88 (m, 2H), 1.83-1.72 (m, 2H). ExampleN-[(5-oxopyrrolidin- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.14 (t, ESI m/z609 3-yl)methyl]-6-{[5- J = 6.2 Hz, 1H), 8.61 (d, J = 3.0 Hz, 1H), 431.1(trifluoromethyl)pyridin- 8.53 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7,2.6 Hz, [M + H]⁺ 2- 1H), 8.21 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 8.4 Hz,yl]oxy}quinoline-2- 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 9.0,carboxamide 2.6 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H),3.49-3.36 (m, 3H), 3.08 (dd, J = 9.7, 4.8 Hz, 1H), 2.81-2.71 (m, 1H),2.27 (dd, J = 16.6, 8.8 Hz, 1H), 2.06-1.94 (m, 1H). ExampleN-(3-acetamido-2- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.02 (t, ESI m/z 610methylpropyl)-6-{[5- J = 6.4 Hz, 1H), 8.61 (d, J = 3.0 Hz, 1H), 447.1(trifluoromethyl)pyridin- 8.53 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7,2.6 Hz, [M + H]⁺ 2- 1H), 8.18 (t, J = 8.2 Hz, 2H), 7.95-7.87 (m,yl]oxy}quinoline-2- 2H), 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.40 (d, J =8.6 Hz, carboxamide 1H), 3.26 (m, 2H), 3.02 (m, 2H), 1.92 (m, 1H), 1.85(s, 3H), 0.88 (d, J = 6.8 Hz, 3H). Example N-methyl-N-[2- ¹H NMR (500MHz, DMSO-d₆) δ ppm ESI m/z 611 (methylsulfonyl)ethyl]- 8.63-8.57 (m,1H), 8.49 (d, J = 8.5 Hz, 1H), 454.1 6-{[5- 8.31 (dd, J = 8.7, 2.6 Hz,1H), 8.15 (m, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 7.90 (d, J = 2.6Hz, 1H), 7.81-7.66 (m, 2H), 2- 7.40 (dd, J = 8.7, 2.4 Hz, 1H), 3.94 (t,J = 7.1 Hz, yl]oxy}quinoline-2- 1H), 3.89-3.82 (m, 1H), 3.81-3.74 (m,1H), carboxamide 3.56 (t, J = 7.1 Hz, 1H), 3.12 and 3.10 (2s, 3H), 3.07and 2.97 (2s, 3H). Example N-[4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.01(t, ESI m/z 612 (methylsulfonyl)butyl]- J = 6.1 Hz, 1H), 8.61 (d, J =3.1 Hz, 1H), 468.1 6-{[5- 8.53 (d, J = 8.5 Hz, 1H), 8.31 (dd, J = 8.7,2.6 Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 8.23-8.15 (m, 2H), 7.93(d, J = 2.6 Hz, 2- 1H), 7.90-7.72 (m, 1H), 7.40 (d, J = 8.7 Hz,yl]oxy}quinoline-2- 1H), 3.42 (m, 2H), 3.22-3.11 (m, 2H), carboxamide2.95 (s, 3H), 1.84-1.59 (m, 4H). Example N-(3- ¹H NMR (500 MHz, DMSO-d₆)δ ppm 8.99 (t, ESI m/z 613 acetamidopropyl)-6- J = 6.1 Hz, 1H),8.64-8.59 (m, 1H), 8.53 (d, J = 8.5 Hz, 433.1 {[5- 1H), 8.31 (dd, J =8.7, 2.6 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 8.22-8.14 (m, 2H),7.95-7.86 (m, 2H), 2- 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.41 (d, J = 8.7Hz, yl]oxy}quinoline-2- 1H), 3.37 (m, 2H), 3.19-3.07 (m, 2H),carboxamide 1.82 (s, 3H), 1.70 (m, 2H). Example 1-[(6-{[5- ¹H NMR (500MHz, DMSO-d₆) δ ppm ESI m/z 614 (trifluoromethyl)pyridin- 8.61-8.57 (m,1H), 8.51 (d, J = 8.5 Hz, 1H), 457.1 2- 8.31 (dd, J = 8.7, 2.6 Hz, 1H),8.15 (d, J = 9.1 Hz, [M + H]⁺ yl]oxy}quinolin-2- 1H), 7.91 (d, J = 2.6Hz, 1H), 7.84-7.77 (m, yl)carbonyl]hexahydropyrrolo[1, 1H), 7.73 (dd, J= 9.0, 2.6 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2- 1H), 5.62 (bs, 1H),4.00-3.64 (m, a]pyrimidin-6(2H)- 2H), 3.23 (m, 1H), 3.05-2.96 (m, 1H),one 2.57 (m, 1H), 2.39-2.32 (m, 2H), 2.10-1.96 (m, 2H), 1.86-1.80 (m,1H). Example N-[2-(1,1- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.06 (t, ESI m/z615 dioxidothietan-3- J = 6.2 Hz, 1H), 8.63-8.59 (m, 1H), 8.53 (d, J =8.5 Hz, 466.1 yl)ethyl]-6-{[5- 1H), 8.32 (dd, J = 8.7, 2.6 Hz, 1H), [M +H]⁺ (trifluoromethyl)pyridin- 8.23-8.15 (m, 2H), 7.93 (d, J = 2.6 Hz,1H), 2- 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.41 (d, J = 8.6 Hz,yl]oxy}quinoline-2- 1H), 4.32-4.21 (m, 2H), 3.96-3.85 (m, carboxamide2H), 3.38 (m, 2H), 2.54 (m, 1H), 1.94 (q, J = 7.0 Hz, 2H). ExampleN-methyl-N-(2,2,2- ¹H NMR (500 MHz, DMSO-d_(6,) rotamers) δ MS 616trifluoroethyl)-6-{[5- ppm 8.62-8.57 (m, 1H), 8.54-8.49 (m, 1H), (ESI)(trifluoromethyl)pyridin- 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (dd, J =19.7, m/z 2- 9.1 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 430.0yl]oxy}quinoline-2- 7.80 (d, J = 8.5 Hz, 0.4H), 7.77-7.71 (m, [M + H]⁺carboxamide 1.6H), 7.40 (dd, J = 8.7, 4.1 Hz, 1H), 4.78 (q, J = 9.4 Hz,1H), 4.46 (q, J = 9.7 Hz, 1H), 3.20 (s, 1H), 3.17 (s, 2H). Example6-{[5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 617(difluoromethyl)pyridin- 2.51-2.81 (m, 4H), 4.02-4.14 (m, 0.5H), 388.02-yl]oxy}-N-(3- 4.65-4.77 (m, 0.5H), 4.84 (p, J = 6.9 Hz, 0.25H), [M +H]⁺ fluorocyclobutyl)quinoline- 4.96 (p, J = 6.8 Hz, 0.25H), 5.28 (tt, J= 6.2, 2-carboxamide 3.1 Hz, 0.25H), 5.40 (tt, J = 6.2, 3.2 Hz, 0.25H),7.13 (t, J = 55.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.69-7.77 (m, 1H),7.88 (d, J = 2.6 Hz, 1H), 8.14 (dd, J = 8.5, 2.9 Hz, 2H), 8.22 (d, J =9.1 Hz, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.52 (dd, J = 8.6, 1.6 Hz, 1H),9.19-9.27 (m, 1H) Example [4-fluoro-4- ¹H NMR (500 MHz, DMSO-d₆) δ ppmDCI m/z 618 (methoxymethyl)piperidin- 1.67-1.88 (m, 3H), 1.93 (t, J =11.8 Hz, 1H), 464.0 1-yl](6-{[5- 3.17 (td, J = 12.8, 3.2 Hz, 1H),3.27-3.36 (m, 4H), [M + H]⁺ (trifluoromethyl)pyridin- 3.42-3.52 (m, 2H),3.68 (d, J = 13.9 Hz, 1H), 2- 4.39 (d, J = 13.2 Hz, 1H), 7.39 (d, J =8.7 Hz, yl]oxy}quinolin-2- 1H), 7.71 (dd, J = 8.8, 2.3 Hz, 2H), 7.89 (d,J = 2.7 Hz, yl)methanone 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.30 (dd, J =8.7, 2.5 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.59 (dd, J = 1.5, 0.7 Hz,1H) Example [3-(2,2- ¹H NMR (500 MHz, DMSO-d₆) δ ppm DCI m/z 619difluoroethoxy)azetidin- 3.77 (td, J = 15.3, 3.6 Hz, 2H), 3.98 (ddd, J =11.3, 454.0 1-yl](6-{[5- 3.7, 1.4 Hz, 1H), 4.36 (ddd, J = 11.1, 6.5, 1.4Hz, [M + H]⁺ (trifluoromethyl)pyridin- 1H), 4.49-4.58 (m, 1H), 4.58-4.66(m, 2- 1H), 4.95 (ddd, J = 11.1, 6.2, 1.3 Hz, 1H), yl]oxy}quinolin-2-6.21 (tt, J = 54.8, 3.6 Hz, 1H), 7.40 (d, J = 8.7 Hz, yl)methanone 1H),7.74 (dd, J = 9.1, 2.6 Hz, 1H), 7.90 (d, J = 2.6 Hz, 1H), 8.06 (d, J =8.5 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H),8.49 (d, J = 8.5 Hz, 1H), 8.60 (dd, J = 1.5, 0.7 Hz, 1H) Example1,1-dimethyl-4-[(6- ¹H NMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 620 {[5-3.41-3.52 (m, 2H), 3.52-3.65 (m, 2H), 4.03 (ddd, J = 20.3, 559.0(trifluoromethyl)pyridin- 12.0, 3.6 Hz, 4H), 4.80-5.19 (m, 6H), [M + H]⁺2- 7.41 (d, J = 8.7 Hz, 1H), 7.70-7.83 (m, 2H), yl]oxy}quinolin-2- 7.93(d, J = 2.6 Hz, 1H), 8.12 (t, J = 7.1 Hz, yl)carbonyl]piperazin- 1H),8.32 (dd, J = 8.7, 2.5 Hz, 1H), 8.55 (dd, J = 16.8, 1-ium iodide 8.2 Hz,2H) Example {3-[(2,2,2- ¹H NMR (500 MHz, DMSO-d₆) δ ppm MS 621trifluoroethyl)amino]azetidin- 8.61-8.58 (m, 1H), 8.48 (d, J = 8.5 Hz,1H), (ESI) 1-yl}(6-{[5- 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (d, J = 9.1Hz, m/z (trifluoromethyl)pyridin- 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.89(d, J = 2.6 Hz, 471.1 2- 1H), 7.73 (dd, J = 9.1, 2.6 Hz, 1H), [M + H]⁺yl]oxy}quinolin-2- 7.40 (d, J = 8.7 Hz, 1H), 4.90-4.84 (m, 1H),yl)methanone 4.43 (dd, J = 10.6, 5.2 Hz, 1H), 4.27 (dd, J = 9.7, 8.1 Hz,1H), 3.88-3.82 (m, 1H), 3.80-3.71 (m, 1H), 3.30-3.26 (m, 2H). ExampleN-(2,2-difluoroethyl)- ¹H NMR (500 MHz, DMSO-d₆, rotamers) δ MS 622N-methyl-6-{[5- ppm 8.61-8.56 (m, 1H), 8.50 (dd, J = 8.5, 2.2 Hz, (ESI)(trifluoromethyl)pyridin- 1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), m/z 2-8.14 (dd, J = 9.1, 3.4 Hz, 1H), 7.91-7.88 (m, 1H), 412.0yl]oxy}quinoline-2- 7.77 (d, J = 8.5 Hz, 0.5H), 7.75-7.70 (m, [M + H]⁺carboxamide 1.5H), 7.40 (d, J = 8.7 Hz, 1H), 6.62-6.21 (m, 1H),4.08-3.94 (m, 2H), 3.16 (s, 1.5H), 3.13 (s, 1.5H). Example 7-oxa-2- ¹HNMR (400 MHz, DMSO-d₆) δ ppm DCI m/z 623 azaspiro[3.5]non-2- 1.69-1.84(m, 4H), 3.47-3.63 (m, 4H), 3.89 (s, 444.0 yl(6-{[5- 2H), 4.50 (s, 2H),7.40 (d, J = 8.7 Hz, 1H), [M + H]⁺ (trifluoromethyl)pyridin- 7.73 (dd, J= 9.1, 2.6 Hz, 1H), 7.89 (d, J = 2.6 Hz, 2- 1H), 8.06 (d, J = 8.6 Hz,1H), 8.18 (d, J = 9.1 Hz, yl]oxy}quinolin-2- 1H), 8.31 (dd, J = 8.7, 2.5Hz, 1H), yl)methanone 8.48 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 0.8 Hz, 1H)

Determination of Biological Activity

Abbreviations: CC2-DMPE forN-(6-chloro-7-hydroxycoumarin-3-carbonyl)-dimyristoylphosphatidylethanolamine;DiSBAC₂(3) for bis(1,3-diethylthiobarbiturate)trimethine oxonol; DMEMfor Dulbecco's Modified Eagle Media; EGTA for ethylene glycoltetraacetic acid; FBS for Fetal Bovine Serum; FLIPR® for FluorometricImaging Plate Reader; FRET for Fluorescence Resonance Energy Transfer;HI FBS for Heat-Inactivated Fetal Bovine Serum; HBSS for Hank's BalancedSalt Solution; HEPES for N-2-HydroxyEthylPiperazine-N′-2-Ethane Sulfonicacid; K-aspartate for potassium aspartate; MEM for Minimal EssentialMedia; MgATP for magnesium adenosine triphosphate; and VABSC-1 forVoltage Assay Background Suppression Compound.

FRET-Based Membrane Potential Assays.

Recombinant, Human Sodium Channel, Na_(v)1.7.

Two days prior to the experiment, frozen HEK293 cells stably expressingrecombinant human Na_(v)1.7 were quickly thawed and plated at 25,000cells/well in growth medium [DMEM (Invitrogen #11965) with 10% HI FBS(Invitrogen #10082), 2 mM glutamine, 100 units/mL penicillin, 0.1 mg/mLstreptomycin (PSG, Sigma #G¹¹⁴⁶), and 500 μg/mL Geneticin (Invitrogen#10131)] in black-walled, clear-bottom 384-well poly-D-lysine-coatedassay plates (Greiner Bio-One, Frickenhausen, Germany) and incubated ina humidified 5% CO₂ incubator at 37° C. On the day of the assay, mediumwas removed by aspiration, and cells were washed with assay buffer [HBSS(Invitrogen, Carlsbad, Calif.) containing 20 mM HEPES (Invitrogen,Carlsbad, Calif.)]. After washing, 30 μL assay buffer containing thefluorescent voltage-sensor probe CC2-DMPE (Invitrogen, Carlsbad, Calif.)at 20 μM and 0.01% pluronic F-127 (Invitrogen, Carlsbad, Calif.) wasadded to the cells. Cells were incubated for 40 minutes at roomtemperature in the dark. Following the incubation, the cells were washedand 30 μL assay buffer containing 2.5 μM DiSBAC₂(3) substrate(Invitrogen, Carlsbad, Calif.) and 0.5 mM VABSC-1 (Invitrogen, Carlsbad,Calif.) was added to the cells. The cells were incubated for 90 minutesat room temperature in the dark. Fluorescence readings were made using aFLIPR®^(TETRA) (Molecular Devices, Sunnyvale Calif.) equipped withvoltage-sensor probe optics. At the start of each experiment the optimal(EC₈₀) concentration of depolarizing agent (veratridine) was determinedby testing a dilution curve of assay buffer containing veratridine(Sigma-Aldrich, St. Louis, Mo.) and 1 mg/mL scorpion venom (SVqq, fromLeiurus quinquestriatus; Sigma-Aldrich, St. Louis, Mo.). Compounds weredissolved in dimethyl sulfoxide, and 8-point, 1:3 dilutionconcentration-response curves were prepared in duplicate in dimethylsulfoxide, followed by preparation of 0.8 uL/well daughter plates of thedilutions. Test compounds in the daughter plate were diluted to (˜3×)solutions in assay buffer immediately before assaying. Using theFLIPR®^(TETRA), 20 pt of the (3×) compound solutions were first added tothe cells, then 20 μL of depolarizing solution (3×EC₈₀ veratridine+SVqq)were added 3 minutes later to activate the channel. Changes influorescence were measured at wavelengths of 440-480 nm and 565-625 nmover the course of the experimental run. Membrane depolarization wasexpressed as a ratio of the maximum F_(440-480 nm)/F_(565-625 nm)reading above average baseline F_(440-480 nm)/F_(565-625 nm) reading.IC₅₀ values were calculated from curve fits of the ratio data using afour-parameter logistic Hill equation (Accelrys Assay Explorer 3.3Client, Accelrys, San Diego, Calif.) with percent inhibition plottedagainst compound concentration.

Data reported in Table 1.

Recombinant, Human Sodium Channel, Na_(v)1.8.

Two days prior to the experiment, frozen HEK293 cells stably expressingrecombinant human Na_(v)1.8 (Essen, Ann Arbor, Mich.) were quicklythawed and plated at 22,500 cells/well in growth medium [MEM (Invitrogen#11095) with 10% FBS (Invitrogen #10082), 1 mM sodium pyruvate(Invitrogen, #C11360), 10 units/mL penicillin/10 U/mL streptomycin/29.2μg/mL glutamine ((PSG 1%, Invitrogen #10378), 400 μg/mL zeocin(Invitrogen #R250) in black-walled, clear-bottom 384-wellpoly-D-lysine-coated assay plates (Greiner Bio-One, Frickenhausen,Germany) and incubated in a humidified 5% CO₂ incubator at 37° C. On theday of the assay, medium was removed by aspiration, and cells werewashed with assay buffer [HBSS (Invitrogen, Carlsbad, Calif.) containing20 mM HEPES (Invitrogen, Carlsbad, Calif.)]. After washing, 30 μL assaybuffer containing the fluorescent voltage-sensor probe CC2-DMPE(Invitrogen, Carlsbad, Calif.) at 20 μM and 0.01% pluronic F-127(Invitrogen, Carlsbad, Calif.) was added to the cells. Cells wereincubated for 40 minutes at room temperature in the dark. Following theincubation, the cells were washed and 30 μL assay buffer containing 2.5μM DiSBAC₂(3) substrate (Invitrogen, Carlsbad, Calif.) and 0.5 mMVABSC-1 (Invitrogen, Carlsbad, Calif.) was added to the cells. The cellswere incubated for 60 minutes at room temperature in the dark.Fluorescence readings were made using a FLIPR®^(TETRA) (MolecularDevices, Sunnyvale Calif.) equipped with voltage-sensor probe optics.The depolarizing agent, veratridine (Sigma-Aldrich, St. Louis, Mo.), wasmade up at 3× concentrations in assay buffer containing 1 mg/mL scorpionvenom (SVqq, from Leiurus quinquestriatus; Sigma-Aldrich, St. Louis,Mo.). The assay agonist/opener concentration was determined each dayusing a 6-point veratridine concentration curve in duplicate, testedwith three concentrations of tetracaine (0.1, 0.06, 0.01 μM all in 0.03%dimethyl sulfoxide) and 0.03% dimethyl sulfoxide control in assaybuffer. The concentration of veratridine chosen for the assay, the“EC₈₀”, was where the assay achieved maximum signal with the dimethylsulfoxide control, minimal inhibition with 0.01 tetracaine, 50%inhibition with 0.06 μM tetracaine, and >50% inhibition with 0.1 μMtetracaine. Compounds were dissolved in dimethyl sulfoxide, and 8-point,1:3 dilution concentration-response curves were prepared in duplicate indimethyl sulfoxide, followed by preparation of 0.8 uL/well daughterplates of the dilutions. Test compounds in the daughter plate werediluted to (˜3×) solutions in assay buffer immediately before assaying.Using the FLIPR®^(TETRA), 20 μL of the (3×) compound solutions werefirst added to the cells, then 20 μL of depolarizing solution (3×EC₈₀veratridine+SVqq) were added 3 minutes later to activate the channel.Changes in fluorescence were measured at wavelengths of 440-480 nm and565-625 nm over the course of the experimental run. Membranedepolarization was expressed as a ratio of the maximumF_(440-480 nm)/F_(565-625 nm) reading above average baselineF_(440-480 nm)/F₅₆₅-625 nm reading. IC₅₀ values were calculated fromcurve fits of the ratio data using a four-parameter logistic Hillequation (Accelrys Assay Explorer 3.3 Client, Accelrys, San Diego,Calif.) with percent inhibition plotted against compound concentration.

Data reported in Table 1.

TABLE 1 FRET-Based membrane potential assays for human sodium channels,Na_(v)1.7 and Na_(v)1.8. FRET-Membrane Potential FRET-Membrane PotentialExample Nav1.7 IC₅₀ (μM) Nav1.8 IC₅₀ (μM) 1 0.911 1.55 2 0.504 0.648 31.45 4 0.856 5 0.262 6 2.93 4.61 7 1.7 8 0.232 9 2.08 10 4.6 2.53 111.61 1.69 12 0.348 13 0.454 14 2.37 15.1 15 1.09 16 0.406 17 3.12 18 2.25.34 19 1.26 3.96 20 10.5 3.23 21 0.529 22 1.98 3.54 23 1.45 >20.0 241.58 25 1.75 3.83 26 1.99 27 1.1 28 3.06 4.22 29 0.79 30 0.793 31 0.6191.86 32 0.535 33 0.471 0.74 34 0.841 35 1.27 36 0.727 1.42 37 0.392 380.311 39 0.735 40 0.285 41 1.27 42 1.79 43 3.06 44 1.67 0.937 45 0.3250.468 46 0.344 0.501 47 1.42 0.334 48 4.43 0.774 49 2.27 0.702 50 12.251 2.25 4.06 52 2.98 3.85 53 3.26 11.0 54 0.409 55 0.594 2.08 56 3.011.49 57 3.19 0.87 58 1.03 2.84 59 1.7 1.53 60 1.26 61 0.556 1.14 62 0.500.12 63 0.976 1.16 64 0.382 0.491 65 2.25 4.23 66 0.883 1.18 67 1.281.75 68 1.21 1.89 69 0.895 2.32 70 1.25 0.821 71 1.81 1.64 72 2.73 3.8473 1.44 1.7 74 0.863 1.88 75 0.944 76 >20.0 77 >20.0 78 >20.0 79 >20.080 >20.0 81 1.87 82 0.222 83 >20.0 84 >20.0 85 0.238 86 1.74 87 1.2388 >20.0 89 1.52 90 0.368 91 3.25 92 9.83 93 1.55 94 5.25 95 4.87 960.329 97 0.842 98 0.885 99 5.05 100 0.221 101 >20.0 102 >20.0 103 >20.0104 >20.0 105 7.25 106 2.42 107 4.12 108 2.41 109 0.66 110 1.96111 >20.0 112 1.48 113 0.741 114 0.56 115 11.2 116 1.03 117 2.23 1182.27 119 0.819 120 2.04 121 1.66 122 2.49 123 6.55 124 2.14 125 3.46 1268.76 127 4.07 128 2.85 129 2.58 130 2.05 131 1.15 132 2.7 133 1.17 1342.32 135 0.688 136 0.533 137 8.24 138 2.47 139 >20.0 140 0.559 141 >20.0142 0.766 143 1.08 144 0.832 145 3.09 146 8.03 147 4.28 148 12.1 1490.981 150 2.28 151 0.792 152 2.07 153 3.3 154 2.32 155 5.38 156 >20.0157 >20.0 158 >20.0 159 0.73 160 0.71 161 >20.0 162 >20.0 163 >20.0 16412.7 165 >20.0 166 11.1 167 2.91 168 >20.0 169 17.2 170 8.87 171 7.95172 10.5 173 0.833 174 0.294 175 0.206 176 8.77 177 2.68 178 0.523 1790.684 180 0.675 181 3.47 182 0.69 183 >20.0 184 0.923 185 >20.0 186 3.97187 >20.0 188 9.53 189 15.1 190 12.1 191 >20.0 192 17.7 193 4.25 1942.55 195 7.6 196 4.93 197 2.72 198 2.21 199 2.55 200 >20.0 201 >20.0 2020.911 203 >20.0 204 1.63 205 3.17 206 >20.0 207 3.65 208 3.05 209 8.86210 >20.0 211 1.93 212 >20.0 213 9.4 214 >20.0 215 0.81 216 1.67 2171.04 218 >20.0 219 2.56 220 2.0 221 2.79 222 2.15 223 2.79 224 >20.0225 >20.0 226 >20.0 227 2.94 228 1.15 229 7.12 230 0.259 231 0.783 23217.4 233 0.586 234 2.87 235 2.36 236 1.01 237 3.07 238 1.54 239 >20.0240 2.01 241 1.85 242 >20.0 243 >20.0 244 >20.0 245 4.63 246 19.8 24713.3 248 17.3 249 0.902 250 1.39 251 1.59 252 >20.0 253 >20.0 254 13.8255 12.1 256 16.4 257 10.6 258 6.13 259 2.06 260 1.04 261 6.31 262 2.09263 0.402 264 3.21 265 3.45 266 5.76 267 10.2 268 2.98 269 3.07 270 3.08271 11.2 272 2.99 273 0.488 274 0.304 275 11.4 276 3.1 277 3.09 278 3.72279 5.68 280 0.605 281 1.28 282 8.52 283 10.9 284 8.59 285 0.774 28611.4 287 2.81 288 7.88 289 3.91 290 9.86 291 13.7 292 3.26 293 3.32 2941.4 295 3.2 296 12.4 297 7.99 298 12.3 299 >20.0 300 >20.0 301 3.12 1.4302 3.49 303 5.68 304 >20.0 305 13.6 306 14.8 307 14.6 308 3.07 309 3.57310 0.665 311 3.11 312 6.93 313 14.0 314 0.218 315 6.12 316 12.0 3173.01 318 7.41 319 0.285 320 17.1 321 8.07 322 12.0 323 >20.0 324 5.01325 8.58 326 3.15 327 0.557 328 >20.0 329 9.28 330 2.95 331 2.64 33210.1 333 >20.0 334 3.44 335 0.573 336 0.439 337 1.66 338 0.984 339 14.4340 2.9 341 4.23 342 3.38 343 >20.0 344 2.1 0.67 345 9.15 346 2.5 3472.63 348 3.9 349 3.25 350 >20.0 351 3.6 352 3.28 353 3.63 354 12.4 3551.27 356 3.36 357 2.72 358 1.31 359 4.71 360 1.09 361 2.88 362 1.0 3631.19 364 0.37 365 0.356 366 3.18 367 2.53 368 1.25 369 15.2 370 3.39 3711.46 372 >20.0 373 3.7 374 0.97 375 13.2 376 3.06 377 3.32 378 2.23 3793.39 380 3.0 381 3.41 382 1.82 383 >20.0 384 1.93 385 2.33 386 >20.0 3872.48 388 >20.0 389 9.22 390 2.34 391 0.687 392 7.96 393 0.399 394 0.443395 >20.0 396 1.94 397 0.896 398 6.11 399 0.375 400 1.22 401 0.40 4029.07 403 9.67 404 1.95 405 1.4 406 1.06 407 3.81 408 >20.0 409 0.403 4100.557 411 14.1 412 0.513 413 12.4 414 5.02 415 1.61 416 0.70 417 11.52.75 418 0.539 419 11.9 420 2.43 421 1.06 422 0.617 423 0.83 424 1.31425 9.09 426 0.972 427 >20.0 428 10.3 429 13.8 430 3.45 431 1.06 0.382432 2.87 433 0.442 434 5.58 435 12.6 436 1.74 3.42 437 3.17 438 12.5 4395.86 440 12.6 441 1.15 442 5.52 443 0.703 444 1.4 445 0.268 446 0.166447 0.69 448 0.371 449 0.789 450 3.58 451 5.23 452 3.21 453 0.405 4543.14 455 >20.0 456 0.886 457 >20.0 458 1.19 459 8.69 460 2.4 461 0.354462 0.947 463 1.12 464 >20.0 465 >20.0 466 9.41 467 0.521 468 13.8 4691.71 470 6.6 471 2.4 472 7.76 473 16.2 474 9.1 475 1.96 476 3.92 4775.51 478 5.94 479 3.19 480 19.9 481 2.63 482 0.569 483 3.61 484 0.879485 3.14 486 2.54 487 0.919 488 0.526 489 1.1 490 1.42 491 4.99 4920.858 493 0.802 494 9.32 495 1.69 496 2.91 497 3.43 498 0.923 499 0.938500 0.293 501 0.734 502 0.429 503 0.586 504 0.593 505 4.94 2.3 506 0.781507 2.18 508 3.65 509 2.64 510 7.29 511 1.98 512 0.983 0.213 513 0.911514 12.9 515 4.25 516 2.0 517 0.37 518 0.998 519 1.16 520 0.945 521 2.631.1 522 10.7 523 0.356 524 1.08 525 6.65 526 3.09 527 5.91 528 2.92 52910.3 >20.0 530 0.911 531 3.57 532 2.77 533 2.4 534 1.97 535 >20.0 5361.15 537 2.71 538 3.16 539 >20.0 540 4.03 541 1.19 542 14.5 543 0.398544 3.45 545 3.7 546 10.1 547 3.29 548 4.05 549 2.49 550 10.7 551 2.77552 0.615 553 0.949 554 14.1 555 2.7 556 2.81 557 16.7 558 4.49 559 3.02560 2.87 561 3.47 562 >20.0 563 >20.0 564 16.6 565 3.43 566 2.37 5673.28 568 3.26 569 1.21 570 0.977 571 0.448 572 2.7 573 0.987 574 0.295575 12.1 576 10.1 577 10.1 578 1.07 579 1.69 580 1.56 1.14 581 12.6 58210.3 583 0.96 584 0.304 585 >20.0 586 1.8 587 1.02 588 3.64 589 4.07 5901.0 591 0.737 592 3.44 593 0.238 594 7.59 595 1.13 596 1.76 597 3.29 5982.98 599 1.59 600 1.76 601 2.51 602 1.07 603 1.95 3.67 604 3.01 605 2.88606 0.856 607 0.91 608 2.7 609 4.5 610 2.76 611 4.99 612 2.93 613 2.21614 12.2 615 2.32 616 2.63 617 2.78 618 2.69 619 2.88 2.91620 >20.0 >20.0 621 2.69 1.65 622 5.4 2.28 623 4.91 3.7

Osteoarthritic (OA) Pain Induced by Sodium Monoiodoacetate (MIA)

Pain behavior was assessed by measurement of hind limb grip force (GF)in adult osteoarthritic rats. Male Sprague Dawley rats, obtained fromCharles River Laboratories, (Wilmington, Mass.), weighing 150-175 g,were injected in the unilateral knee join with a single intra-articularinjection of sodium monoiodoacetate (MIA, 3 mg/rat). All rats weretested at 20 days following MIA injection. A behavioral measure ofactivity-induced pain was carried out. Measurements of the peak hindlimb grip force were conducted by recording the maximum compressiveforce (CFmax), in grams of force, exerted on a hind limb strain gaugesetup, in a commercially available grip force measurement system(Columbus Instruments, Columbus, Ohio).

During testing, each rat was gently restrained by grasping it around itsrib cage and then allowed to grasp the wire mesh frame attached to thestrain gauge. The experimenter then moved the animal in arostral-to-caudal direction until the grip was broken. Each rat wassequentially tested twice at an approximately 2-3 minute interval toobtain a raw mean grip force (CFmax). This raw mean grip force data wasin turn converted to a maximum hindlimb cumulative compressive force(CFmax), as the grams of force/kg of body weight, for each animal.

For evaluating the compound effects, the hind limb grip force wasconducted 20 days following the intra-articular injection of MIA. Agroup of age-matched naïve (not injected with MIA) animals was added asa comparator to the drug-dosed groups. The vehicle control response foreach group of MIA-treated animals was defined as the 0% response (0%effect), whereas the naïve control group was defined as the normalresponse and as 100% effect. The % effect for each dose group wasexpressed as % return of response to normalcy, compared to the naïvegroup. A percent maximal possible effect (% MPE) of testing compound wascalculated according to the formula: (Treatment CFmax VehicleCFmax)/Vehicle CFmax]×100). Higher % effect numbers indicate increasedrelief from the pain in the model, with 100% indicating a return to thelevel of response seen in normal (non-osteoarthritic) animals. Allexperiments evaluating drug effects in this model were conducted in arandomized blinded fashion.

The animals were housed in Association for Assessment and Accreditationof Laboratory Animal Care (AAALAC) approved facilities at AbbVie Inc. ina temperature-regulated environment under a controlled 12-hourlight-dark cycle, with lights on at 6:00 a.m. Food and water wereavailable ad libitum at all times except during testing. All testing wasdone following procedures outlined in protocols approved by AbbVieInc.'s Institutional Animal Care and Use Committee.

Data reported in Table 2.

Rat Spinal Nerve Ligation (SNL) Model of Neuropathic Pain.

A model of spinal nerve ligation-induced (SNL model) neuropathic pain asoriginally described by Kim and Chung (Kim, S. H. and J. M. Chung, 1992,Pain 50, 355) was used to test a compound of the present application.The male Sprague Dawley rats (Charles River Laboratories, Wilmington,Mass.), weighing 150-175 g at the time of surgery, were placed underisoflurane anesthesia and a 1.5 cm incision was made dorsal to thelumbosacral plexus. The paraspinal muscles (left side) were separatedfrom the spinous processes, the left L5 and L6 spinal nerves isolated,and tightly ligated with 5-0 silk suture distal to the dorsal rootganglion. Care was taken to avoid ligating the L4 spinal nerve.Following spinal nerve ligation, a minimum of 7 days of recovery and nomore than 3 weeks was allowed prior to the behavioral testing(mechanical sensitivity). Only rats with threshold scores ≤4.5 g wereconsidered allodynic and utilized in pharmacological experiments.

Mechanical sensitivity was measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.). Paw withdrawal threshold (PWT) wasdetermined by using the Dixon's up-down method (Dixon, W. J., 1980, Ann.Rev. Pharmacol. Toxicol., 20, 441). Rats were placed into invertedindividual plastic containers (20×12.5×20 cm) on top of a suspended wiremesh with a 1 cm² grid to provide access to the ventral side of the hindpaws, and acclimated to the test chambers for 20 minutes. The von Freyfilaments were presented perpendicularly to the plantar surface of theselected hind paw, and then held in this position for approximately 8seconds with enough force to cause a slight bend in the filament.Positive responses included an abrupt withdrawal of the hind paw fromthe stimulus, or flinching behavior immediately following removal of thestimulus. A 50% withdrawal threshold was determined using an up-downprocedure (Dixon, 1980). A percent maximal possible effect (% MPE) oftesting compound was calculated according to the formula: (Log[compound−treated threshold]−Log [vehicle−treated threshold])/(Log[maximum threshold]−Log [vehicle-treated threshold])×100%, where themaximum threshold was equal to 15 g.

The animals were housed in Association for Assessment and Accreditationof Laboratory Animal Care (AAALAC) approved facilities at AbbVie Inc. ina temperature-regulated environment under a controlled 12-hourlight-dark cycle, with lights on at 6:00 a.m. Food and water wereavailable ad libitum at all times except during testing. All testing wasdone following procedures outlined in protocols approved by AbbVieInc.s' Institutional Animal Care and Use Committee.

Data reported in Table 2.

TABLE 2 In vivo data for MIA-OA and SNL pain assays. OA Dose SNL DoseExample (mg/kg) OA MPE (%) (mg/kg) SNL MPE (%) 1 30 64 100 49 2 30 85100 54 3 30 46 4 30 60 100 56 5 30 27 6 10 72 100 27 7 30 51 8 30 91 910 68 10 30 48 100 35 11 10 72 100 34 12 10 79 13 10 44 14 30 81 100 4415 10 52 16 10 57 17 10 19 18 10 23 19 30 64 20 10 24 21 10 35 22 30 73100 72 23 30 83 24 10 62 25 30 102 26 10 67 27 10 49 28 10 16 29 10 2030 10 66 31 30 94 100 64 32 10 23 33 30 61 100 50 34 10 41 35 10 79 10074 36 10 55 37 10 29 38 10 30 39 30 43 40 10 59 41 10 67 42 10 64 43 1071 44 10 42 45 30 17 46 30 98 47 10 30 48 10 41 49 30 58 50 30 81 100 9451 30 52 100 90 52 30 86 100 81 53 30 70 54 10 21 55 10 42 56 10 43 5730 53 58 30 64 59 30 83 100 84 60 10 23 61 10 61 62 10 −1 63 10 15 64 1029 65 30 63 66 30 52 67 10 43 68 10 52 69 10 2 70 10 23 71 10 33 72 3011 73 30 66 74 30 69 301 30 58 344 30 59 100 76 431 30 73 436 30 51 44110 22 483 10 55 505 30 52 616 30 28 619 30 53

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, or methods, or anycombination of such changes and modifications of use of the invention,may be made without departing from the spirit and scope thereof.

1-26. (canceled)
 27. A method of treating a condition or disordermodulated by the voltage-gated sodium channels Na_(v)1.7 and/orNa_(v)1.8 in a mammal comprising administering an effective amount of[(3R)-3-fluoropyrrolidin-1-yl](6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinolin-2-yl)methanone,or a pharmaceutically acceptable salt thereof.
 28. (canceled)